6-substituted pyrazolo [3,4-d] pyrimidin-4-ones useful as cyclin dependent kinase inhibitors

ABSTRACT

The present invention relates to the synthesis of a novel class of pyrazolo[3,4-d]pyrimidin-4-ones of formula (I), alternatively represented by the tautomer (II):                    
     that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cyclin dependent kinase 1-8 and their regulatory subunits know as cyclins A-H, K, N, and T. 
     This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from provisional U.S. application Ser. No. 60/103,957, filed Oct. 13, 1998, incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates generally to novel 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones which are useful as cyclin dependent kinase (cdk) inhibitors, pharmaceutical compositions comprising the same, methods for using the same for treating cancer and proliferative diseases, and intermediates and processes for making the same.

BACKGROUND OF THE INVENTION

One of the most important and fundamental processes in biology is the division of cells mediated by the cell cycle. This process ensures the controlled production of subsequent generations of cells with defined biological function. It is a highly regulated phenomenon and responds to a diverse set of cellular signals both within the cell and from external sources. A complex network of tumor promoting and suppressing gene products are key components of this cellular signaling process. Overexpression of the tumor promoting components or the subsequent loss of the tumor suppressing products will lead to unregulated cellular proliferation and the generation of tumors (Pardee, Science 246:603-608, 1989).

Cyclin dependent kinases play a key role in regulating the cell cycle machinery. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, eight kinase subunits (cyclin dependent kinase 1-8) have been identified along with several regulatory subunits (cyclins A-H, K, N, and T). Each kinase associates with a specific regulatory partner and together make up the active catalytic moiety. Each transition of the cell cycle is regulated by a particular cyclin dependent kinase complex: G1/S by cyclin dependent kinase2/cyclin E, cyclin dependent kinase4/cyclin D1 and cyclin dependent kinase6/cyclinD2; S/G2 by cyclin dependent kinase2/cyclin A and cyclin dependent kinase1/cyclin A; G2/M by cyclin dependent kinase1/cyclinB. The coordinated activity of these kinases guides the individual cells through the replication process and ensures the vitality of each subsequent generation (Sherr, Cell 73:1059-1065, 1993; Draetta, Trends Biochem. Sci. 15:378-382, 1990).

An increasing body of evidence has shown a link between tumor development and cyclin dependent kinase related malfunctions. Overexpression of the cyclin regulatory proteins and subsequent kinase hyperactivity have been linked to several types of cancers (Jiang, Proc. Natl. Acad. Sci. USA 90:9026-9030, 1993; Wang, Nature 343:555-557, 1990). More recently, endogenous, highly specific protein inhibitors of cyclin dependent kinases were found to have a major affect on cellular proliferation (Kamb et al., Science 264:436-440, 1994; Beach, Nature 336:701-704, 1993). These inhibitors include p16^(INK4) (an inhibitor of cyclin dependent kinase4/D1), p21^(CIP1) (a general cyclin dependent kinase inhibitor), and p27^(KIP1) (a specific cyclin dependent kinase2/E inhibitor). A recent crystal structure of p27 bound to cyclin dependent kinase2/A revealed how these proteins effectively inhibit the kinase activity through multiple interactions with the cyclin dependent kinase complex (Pavletich, Nature 382:325-331, 1996). These proteins help to regulate the cell cycle through specific interactions with their corresponding cyclin dependent kinase complexes. Cells deficient in these inhibitors are prone to unregulated growth and tumor formation.

Schmidt et al. describe in U.S. Pat. No. 3,211,731 (issued Oct. 12, 1965) pyrazolo[3,4-d]pyrimidines of the formula:

where:

R¹ represents hydrogen, alkyl, cycloalkyl, aralkyl, oxalkyl, hydroxyalkyl, halogenoalkyl, cycloalkylalkyl, heteroaralkyl, mono- or binuclear aryl or heteroaryl;

R³ represents hydrogen or lower alkyl;

R⁶ represents substituted or unsubstituted aralkyl or heteroaralkyl.

These compounds are claimed to have utility as coronary dilating agents.

SUMMARY OF THE INVENTION

The present invention describes a novel class of 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones or pharmaceutically acceptable salt or prodrug forms thereof that are potent inhibitors of the class of enzymes known as cyclin dependent kinases.

It is another object of this invention to provide a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of this invention to provide a novel method of treating cancer or other proliferative diseases, which comprises administering a therapeutically effective combination of at least one of the compounds of the present invention and at least one other known anti-cancer or anti-proliferative agent.

These and other objectives, which will become apparant during the following detailed descriptions, have been achieved by the inventors, discovery that compounds of formula (I), alternatively represented by the tautomer (II):

wherein R¹, R², R³, R⁴, R⁵, Q, Y, and Z are defined below or pharmaceutically acceptable salts thereof, are cyclin dependent kinase inhibitors.

As described herein, the inhibitors of this invention are capable of inhibiting the cell-cycle machinery and consequently would be useful in modulating cell-cycle progression, which would ultimately control cell growth and differentiation. Such compounds would be useful for treating subjects having disorders associated with excessive cell proliferation, such as cancer, psoriasis, immunological disorders involving unwanted leukocyte proliferation, in the treatment of restenosis and other smooth muscle cell disorders, and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention, in a first embodiment, describes a novel compound of the formula (I) or its tautomer, formula (II):

or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:

Q is selected from the group: H, OH, and CH₃, and CH₂CH₃;

Y is selected from the group: F, Cl, Br, and I;

Z is selected from the group: N and CR⁶;

R¹ is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-3 R⁷;

R² is selected from the group: C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S—C₁₋₃ alkyl, O—C₁₋₃ alkyl, NH₂, NH—C₁₋₃ alkyl, N(C₁₋₂ alkyl)₂, OCF₃, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH₂CN, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NHC₁₋₃ alkyl, CH₂NMe₂, CF₃, CHO, OCH₂CH₂OH, OCH(Me)CH₂OH, OCH₂CH(Me)OH, OCH₂CH₂NMe₂, and CHF₂;

R³ is selected from the group: H, F, Cl, Br, I, CF₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, CH═CHR^(a), C₁₋₃ alkyl, C₁₋₃ alkoxy, CO₂H, CONH₂, CONH(C₁₋₃ alkyl), CON(C₁₋₃ alkyl)₂, CO₂C₁₋₃ alkyl, C(O)C₁₋₂ alkyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂;

R⁴ is selected from the group: H, F, Cl, Br, I, CF₃, C₁₋₃ alkyl, C₂₋₃ alkenyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂;

R⁵ is selected from the group: H, C₁₋₃ alkyl, F, Cl, Br, I, CF₃, and C₂₋₃ alkenyl;

R⁶ is selected from the group: H, F, Cl, Br, I, CF₃, —NO₂, C₁₋₃ alkyl optionally substituted with 1-2 R, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, CO₂H, CHO, CONR^(a)R^(b), CO₂C₁₋₃ alkyl, C(O)C₁₋₂ alkyl, CH₂NHR^(a), CONR^(g)NR^(a)R^(b), NR^(a)R^(b); SO₂NR^(a)R^(b), CR═NNR^(a)R^(b), CR═NOR^(f), and R^(h);

R⁷ is independently, at each occurrence, selected from the group: OH, C₁₋₆ alkoxy, OC₂₋₆ alkyl-CO₂H, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, I, CF₃, OCF₃, —CN, —NO₂, CO₂H, CO₂(C₁₋₆ alkyl), CONR^(a)R^(b), NR^(g)CONHOR^(g), NR^(g)CONHSO₂R^(a), NHNR^(g)C(O)OR^(a), NR^(g)C(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, —SO₂NR^(a)R^(b), NHSO₂NHCO₂C₁₋₄ alkyl, NR^(g)SO₂NR^(a)R^(b), NR^(g)SO₂CHR^(e)CH₂NR^(a)R^(b), NR^(g)COCHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)NR^(b)CH₂R^(f)R^(a), NR^(g)COCH₂CHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)CH₂NR^(a)R^(b), NR^(g)CO(CH₂)_(m)R^(a)R^(b), NR^(g)CONR^(e)(CH₂)_(n)NR^(a)R^(b), NR^(g)CO₂(CHR^(e))_(n)NR^(a)R^(b), CONR^(e)NR^(a)R^(b), NR^(g)CONR^(e)NR^(a)R^(b), C₃₋₁₀ carbocycle, C₁₋₁₀ alkyl substituted with 0-3 R⁸, NHCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₂₋₁₀ alkenyl substituted with 0-3 R⁸, C₂₋₁₀ alkynyl substituted with 0-3 R⁸, and C₃₋₁₀ heterocycle containing 1-4 heteroatoms selected from O, N, and S;

R³ is independently, at each occurrence, selected from the group: ═O, OH, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, F, Cl, Br, I, CO₂H, COR^(a), CO₂(benzyl), CO₂(C₁₋₆ alkyl), and CONR^(a)R^(b);

R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₁₋₆ alkyl substituted with one R;

R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, CO₂H, OH, and NR^(c)R^(d);

R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom;

alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom;

R^(c) is independently, at each occurrence selected from the group: H, R^(f), and CO₂H;

R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms;

R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe;

R^(g) is independently, at each occurrence, selected from H and C₁₋₃ alkyl;

R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe;

n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and

m at each occurrence is independently selected from 3, 4, 5, and 6.

In a preferred embodiment, the present invention provides a novel compound of the formula (I) or (II), wherein:

Q is selected from the group: H, OH, and CH₃;

Y is selected from the group: F, Cl, and Br;

Z is selected from the group: N and CR⁶;

R¹ is selected from the group: phenyl and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-3 R⁷;

R² is selected from the group: C₂₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S—C₁₋₂ alkyl, O—C₁₋₂ alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, CH₂CN, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NMe₂, CF₃, and CHO;

R³ is independently selected from the group: H, F, Cl, CH₃, CH₂CH₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, and CH═CHR^(a);

R⁴ is independently selected from the group: H, F, Cl, and CH₃;

R⁵ is independently selected from the group: H, CH₃, F, Cl, Br, and CF₃;

R⁶ is independently selected from the group: H, F, Cl, Br, CF₃, C₁₋₃ alkyl optionally substituted with R, CO₂H, CONH₂, CONHR^(a), CONHNR^(a)R^(b), CHO, CH₃, SO₂NR^(a)R^(b); phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH₂NHR^(8a);

R⁷ is independently, at each occurrence, selected from the group: OH, C₁₋₃ alkoxy, OC₂₋₆ alkyl-CO₂H, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, I, CF₃, OCF₃, —CN, CO₂(C₁₋₆ alkyl), CONR^(a)R^(b), NR^(g)C(O)OR^(a), NR^(g)C(O)NR^(a)R^(b), NR^(g)CONHOR^(g), NR^(g)CONHSO₂R^(a), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, SO₂NR^(a)R^(b), NR^(g)SO₂NR^(a)R^(b), NR^(g)SO₂NHCO₂C₁₋₄ alkyl, NR^(g)SO₂CHR^(e)CH₂NR^(a)R^(b), NR^(g)COCHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)NR^(b)CH₂R^(f)R^(a), NR^(g)COCH₂CHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)CH₂NR^(a)R^(b), NR^(g)CO(CH₂)_(m)NR^(a)R^(b), NR^(g)CONR^(e)(CH₂)_(n)NR^(a)R^(b), NR^(g)CO₂(CHR^(e))_(n)NR^(a)R^(b), CONR^(e)NR^(a)R^(b), NR^(g)CONR^(e)NR^(a)R^(b), C₃₋₇ carbocycle, NHCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₁₋₀ alkyl substituted with 0-3 R⁸, C₂₋₆ alkenyl substituted with 0-3 R⁸, C₂₋₆ alkynyl substituted with 0-2 R⁸, and C₃₋₇ heterocycle containing 1-3 heteroatoms selected from O, N, and S;

R⁸ is independently, at each occurrence, selected from the group: ═O, OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, COR^(a), and CONR^(a)R^(b);

R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₁₋₆ alkyl substituted with one R;

R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, CO₂H, and NR^(c)R^(d);

R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing an additional 0-1 N, O, or S atom;

alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom;

R^(c) is independently, at each occurence, selected from the group: H, R^(f), and CO₂H;

R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms;

R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₄ alkyl;

R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe;

R^(g) is independently, at each occurrence, selected from H and C₁₋₃ alkyl;

R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe;

n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and

m at each occurrence is independently selected from 3, 4, 5, and 6.

In a more preferred embodiment, the present invention provides a novel compound of the formula (I) or (II), wherein:

Q is H;

Y is selected from the group: F, Cl, and Br;

Z is CR⁶;

R¹ is selected from the group: phenyl, pyridyl, pyrazyl pyrimidyl, pyridazyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and a 5 membered aromatic heterocycle containing 1-2 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-2 R⁷;

R² is selected from the group: C₂₋₄ alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, and CF₃;

R³ is independently selected from the group: H, F, CH₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, and CH═CHR^(a);

R⁴ is independently selected from the group: H and F;

R⁵ is independently selected from the group: CH₃, F, Cl, and Br;

R⁶ is independently selected from the group: H, F, Cl, Br, CF₃, CH₃, CONH₂, CONHR^(a), CONHNR^(a)R^(b), SO₂NR^(a)R^(b); CH₂OH, CHO, phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH₂NHR^(a);

R⁷ is independently, at each occurrence, selected from the group: OH, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, CF₃, —CN, CONR^(a)R^(b), NHC(O)OR^(a), NHC(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, SO₂NR^(a)R^(b), NHSO₂NR^(a)R^(b), NHCONHOR^(e), NHCONHSO₂R^(f), NHSO₂NHCO₂C₁₋₄alkyl, NHSO₂CHR^(e)CH₂NR^(a)R^(b), NHCOCHR^(e)NR^(a)R^(b), NHCOCHR^(e)NR^(b)CH₂R^(f)R^(a), NHCOCH₂CHR^(e)NR^(a)R^(b), NHCOCHR^(e)CH₂NR^(a)R^(b), NHCO(CH₂)_(m)NR^(a)R^(b), NHCONR^(e)(CH₂)_(n)NR^(a)R^(b), NHCO₂(CHR^(e))_(n)NNR^(a)R^(b), CONR^(e)NR^(a)R^(b), NHCONR^(e)NR^(a)R^(b), NHCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₃₋₇ carbocycle, C₁₋₆ alkyl substituted with 0-3 R⁸, C₂₋₆ alkenyl substituted with 0-3 R⁸, C₂₋₆ alkynyl substituted with 0-3 R⁸, and C₃₋₇ heterocycle containing 1-3 heteroatoms selected from O, N, and S;

R⁸ is independently, at each occurrence, selected from the group: OH, C₁₋₃ alkoxy, NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, and CONR^(a)R^(b);

R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₁₋₆ alkyl substituted with one R;

R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, and NR^(c)R^(d);

R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom;

alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom;

R^(c) is independently, at each occurrence, selected from the group: H and R^(f);

R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-2 additional N, S, or O atoms;

R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₃ alkyl;

R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe;

R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe;

n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and

m at each occurrence is independently selected from 3, 4, 5, and 6.

In an even more preferred embodiment, the present invention provides a novel compound of formula (I) or (II), wherein:

Q is H;

Y is Cl;

Z is CR⁶;

R¹ is selected from the group: phenyl, pyridyl, pyrrolyl, furyl, thienyl, indazolyl, benzoxazolyl, and benzothiazolyl, and R¹ is substituted with 0-2 R⁷;

R² is selected from the group: CF₃, C₂₋₃ alkyl and cyclopropyl;

R³ is selected from the group: H, CH₃, CH₂OH, and CHO;

R⁴ is H;

R⁵ is independently selected from the group: CH₃, F, Cl, and Br;

R⁶ is independently selected from the group: H, F, Cl, Br, CH₃, CONH₂, CONHNR^(a)R^(b), SO₂NR^(a)R^(b); CH₂OH, CHO, CH₂NHR^(a), and CONHR^(a);

R⁷ is independently, at each occurrence, selected from the group: OH, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, NHC(O)OR^(a), NHC(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, CONR^(a)R^(b), NHCONHOR^(e), NHCONHSO₂R^(f), NHSO₂NHCO₂C₁₋₄ alkyl, NHSO₂CHR^(e)CH₂NR^(a)R^(b), NHCOCHR^(e)NR^(a)R^(b), NHCOCHR^(e)NR^(b)CH₂R^(f)R^(a), NHCOCH₂CHR^(e)NR^(a)R^(b), NHCOCHR^(e)CH₂NR^(a)R^(b), NHCO(CH₂)_(m)NR^(a)R^(b), NHCONR^(e)(CH₂)_(n)NR^(a)R^(b), NHCO₂(CHR^(e))_(n)NNR^(a)R^(b), CONR^(e)NR^(a)R^(b), NHCONHNR^(a)R^(b), C₁₋₄ alkyl substituted with 0-1 R⁸, and C₅₋₇ heterocycle containing 1-3 heteroatoms selected from O, N, and S;

R⁸ is independently, at each occurrence, selected from the group: NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, and CONR^(a)R^(b);

R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, and C₁₋₃ alkyl substituted with R;

R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, and NR^(c)R^(d);

R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl;

alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom;

alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom;

R^(c) is independently, at each occurrence, selected from the group: H and R^(f);

R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₃ alkyl;

alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-6 membered ring and containing 0-2 additional N, S, or O atoms;

R^(e) is independently, at each occurence, selected from the group: H and CH₃;

R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe;

n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and

m at each occurrence is independently selected from 3, 4, 5, and 6.

In a further preferred embodiment, the compound of formula (I) or formula (II) is selected from:

a) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-hydroxy-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

b) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

c) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

d) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

e) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

f) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

g) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-acetamidobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

h) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N-(t-butoxycarbonyl)glycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

i) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(2-(N,N-dimethylamino)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

j) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

k) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(pyrid-2-ylmethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

l) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-glycinamidobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

m) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(pyrid-4-ylmethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

n) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(para-biphen-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

o) 1-(2,6-dichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

p) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(4-methylpiperazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

q) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(dimethylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

r) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(2-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

s) 1-(2,6-dichlorophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

t) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(methoxyaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

u) 1-(2,6-dichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

v) 1-(2,6-dichlorophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

w) 1-(2-chloro-6-methylphenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

x) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3,5-dihydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

y) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-hydroxy-3-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

z) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-amino-3-nitrobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aa) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(methylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ab) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-(methanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ac) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(methanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ad) 1-(2,6-dichloro-4-(pyrid-3-ylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]-pyrimidin-4-one;

ae) 1-(2,6-dichloro-4-(pyrid-4-ylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]-pyrimidin-4-one;

af) 1-(2,6-dichloro-4-(cyclopropylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ag) 1-(2,6-dichloro-4-(N-(pyrid-3-ylmethyl)aminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ah) 1-(2,6-dichloro-4-(N-(pyrid-2-ylmethyl)aminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ai) 1-(2,6-dichloro-4-(ethylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aj) 1-(2,6-dichloro-4-(benzylaminocarbonyl)phenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ak) 1-(2,6-dichloro-4-(2-(dimethylamino)ethylaminocarbonyl)phenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

al) 1-(2,6-dichloro-4-(methylaminocarbonyl)phenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

am) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-(N,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

an) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ao) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N-methylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ap) 1-(2,6-dichloro-4-bromophenyl)-3-ethyl-6-(4-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methoxycarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ar) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

as) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

at) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

au) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(methanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

av) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(difluoroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

aw) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(acetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ax) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(methylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ay) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

az) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(azetidin-3-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ba) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-aminoethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bb) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(isopropylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bc) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-fluorobenzylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrrolidin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

be) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrid-2-ylmethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bf) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(t-butoxycarbonylamino)ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrid-3-ylmethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bh) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(pyrid-4-ylmethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bi) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholin-4-yl)ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bj) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(methylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bk) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bl) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylcarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bm) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-methylpyrid-3-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

bn) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bo) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2,2-dimethylhydrazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bp) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxybut-4-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bq) (+/−)1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyprop-1-ylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

br) (+/−)1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxyprop-2-ylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bs) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(pyrid-3-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

bt) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bu) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(dimethylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bv) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(pyrid-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

bw) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bx) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

by) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylaminocarbonylamino)-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

bz) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-(3-(dimethylamino)propyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ca) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(benzoxazol-2-on-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

cb) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylcarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cc) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(2-(dimethylamino)ethyl)aminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylaminocarbonylamino)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ce) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cf) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(morpholin-4-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ch) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(imidazol-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ci) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl-N-(1-methylpiperidin-4-yl)aminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cj) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(cyclopropylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ck) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cl) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cm) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

cn) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(2-(dimethylamino)ethyl)aminomethylcarbonylamino)benzyl)-pyrazolo[3,4-d]pyrimidin-4-one;

co) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylcarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cp) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(azetidin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxy-4-(imidazol-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cr) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cs) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(3-(dimethylamino)prop-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ct) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylhomopiperazin-1-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cu) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-2-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cv) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(t-butoxycarbonylaminosulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cw) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cx) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholin-4-yl)ethylaminothiocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cy) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

cz) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-bromobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

da) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-2-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

db) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1,4-dimethylpiperazin-2-ylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dc) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethylsulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-amino-3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

de) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-hydantoin-3-ylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

df) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(2H-1,4-benzoxazin-3-on-7-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

dg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dh) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

di) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dj) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dk) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-glycinamidobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dl) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dm) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dn) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-(aminomethyl)piperidin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

do) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(homopiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dp) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethylaminomethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(dimethylaminomethyl)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dr) (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ds) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-,N-dimethylalaninamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dt) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1,4,7-triazacyclonon-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

du) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dv) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholin-4-yl)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dw) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N-,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dx) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

dy) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(morpholin-4-ylaminocarbonylamino)benzyl)pyrazolo[3,4]pyrimidin-4-one;

dz) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methoxyaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ea) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methanesulfonamidocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eb) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ec) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl,N-(1-methylpiperidin-4-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ed) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(tetrahydrofur-2-ylmethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ee) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxypent-2-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ef) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1-hydroxyprop-2-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eg) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyprop-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eh) (+/−)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)prop-1-ylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ei) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ej) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(indazol-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

ek) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(indazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

el) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(indazol-4-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

em) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(benzoxazol-2-on-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one;

en) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-nitrobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eo) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ep) 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

eq) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(cis-3,4-dimethylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

er) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(trans-2,5-dimethylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

es) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(3-methylpiperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

et) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(5-(dimethylaminomethyl)-1-methylpyrrol-2-yl)pyrazolo[3,4-d]pyrimidin-4-one;

eu) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbony)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ev) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ew) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N-methyl,N-(1-methylpiperidin-4-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ex) 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N-methyl-N-(1-methylpiperidin-4-yl)aminomethylcarboylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ey) 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(N-methyl,N((3S,4S)-4-dimethylaminotetrahydrofur-3-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ez) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fa) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-pyrrolidin-1-ylethylaminocarbonyamino)benzyl)pyrazolo[3,4-d] pyrimidin-4-one;

fb) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fc) 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(N-(2-(dimethylamino)ethyl)aminocarbonymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fd) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-(2-(dimethylamino)ethyl)aminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fe) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(methylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

ff) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl-N-(1-methylpiperidin-4-yl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fg) 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-methyl, N-(2-(dimethylamino)ethyl)aminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one;

fh) 1-(2,6-dichloro-4-sulfonamidophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one; and

fi) 1-(4-aminomethyl-2, 6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one.

In another embodiment, the present invention provides a novel pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method of treating cancer or other proliferative diseases comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of formula (I) or (II), or a pharmaceutically acceptable salt form thereof.

In another embodiment, the present invention provides a novel method of treating cancer or other proliferative diseases comprising administering to a host in need of such treatment a therapeutically effective amount of:

(a) a compound of formula (I) or (II), or a pharmaceutically acceptable salt form thereof; and,

(b) at least one compound selected from the group consisting of anti-cancer agents and anti-proliferative agents.

DEFINITIONS

As used herein, the following terms and expressions have the indicated meanings. The compounds of the present invention may contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.

The present invention is intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include ¹³C and ¹⁴C.

The term “alkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Examples of alkyl include but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. In addition, the term is intended to include both unsubstituted and substituted alkyl groups, the latter referring to alkyl moieties having one or more hydrogen substituents replaced by, but not limited to, halogen, hydroxyl, carbonyl, alkoxy, ester, ether, cyano, phosphoryl, amino, imino, amido, sulfhydryl, alkythio, thioester, sulfonyl, nitro, heterocyclo, aryl or heteroaryl. It will also be understood by those skilled in the art that the substituted moieties themselves can be substituted as well when appropriate.

The terms “halo” or “halogen” as used herein refer to fluoro, chloro, bromo and iodo. The term “aryl” is intended to mean an aromatic moiety containing the specified number of carbon atoms, such as, but not limited to phenyl, indanyl or naphthyl. The terms “cycloalkyl” and “bicycloalkyl” are intended to mean any stable ring system, which may be saturated or partially unsaturated. Examples of such include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]nonane, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term “aromatic heterocyclic system” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S. It is preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, EtOAc, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

“Prodrugs”, as the term is used herein, are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (i.e., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same, and compositions containing the same. Prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.

“Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties.

The term “therapeutically effective amount” of a compound of this invention means an amount effective to inhibit the class of enzymes known as cyclin dependent kinases or treat the symptoms of cancer or other proliferative diseases in a host.

As used herein, the term “anti cancer” or “anti-proliferative” agent includes, but is not limited to, altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, octreotide, estramustine, and hydroxyurea.

DOSAGE AND FORMULATION

The cyclic dependent kinase inhibitor compounds of this invention can be administered as treatment for cancer or proliferative diseases by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but preferably are administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired. A daily dosage of active ingredient can be expected to be about 0.001 to about 1000 milligrams per kilogram of body weight, with the preferred dose being about 0.1 to about 30 mg/kg.

Dosage forms of compositions suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets and powders, or in liquid dosage forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts, and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, 18 th ed., Mack Publishing Company, Easton, Pa., 1990, a standard reference text in this field, the disclosure of which is hereby incorporated by reference.

SYNTHESIS

The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those methods described below. Each of the references cited below are hereby incorporated herein by reference.

Key intermediates preparing the compounds of the present invention are pyrazole aminonitriles, aminocarboxamides, and aminoesters of the formulas II, III, and IV, respectively. The preparation of these intermediates is has precedence in the chemical literature, and several methods are summarized in Schemes A (A. O. Abdelhamid, A. S. Shawali, et al. J. Heterocycl. Chem., 1984, 21, 1049.), B (C. C. Cheng and R. K. Robins, J. Org. Chem. 1956, 21, 1240.), C (P. Schmidt and J. Druey, Helv. Chem. Acta, 1956, 39, 986.), and D (Tominaga et al., J. Heterocycl. Chem., 1990, 27, 775). A wide variety of starting hydrazines and aldehydes are commercially available or can be prepared by standard organic transformations. The substituents in the following schemes, which are designated R¹, R², and Q, have the same definition as that defined above in the Detailed Description.

Aminonitriles of the formula II can be converted to pyrazolo[3,4-d]pyrimidines of the present invention as shown in Scheme E. In summary, the aminocarboxamide is acylated, optionally in the presence of a suitable solvent such as dichloromethane by treatment with a suitable base such as triethylamine followed by an acid halide of the formula R¹CHQCOX, preferably an acid chloride to give carboxamidonitriles of the formula V. Alternately carboxamidonitriles of the formula V can be prepared by coupling of aminonitriles II with carboxylic acids of the general formula R¹CHQCO₂H in the presence of a suitable base and coupling reagent in a suitable solvent. The coupling of amines and carboxylic acids has been reviewed (Klausnew and Bodansky Synthesis, 1972, 453-463), and the variety of reagents available for effecting it can be appreciated by those skilled in the art.

Transformation of carboxamidonitriles of the formula V to the compounds of the present invention can be accomplished by treatment with an excess of hydrogen peroxide in the presence of a suitable base, preferably a metal hydroxide or alkoxide base in a solvent, preferably water, an alcohol, or a water-alcohol mixture at a temperature in the range of about 0° C. up to 100° C.

Alternatively, carboxamidonitriles of the formula V can be transformed to the compounds of the present invention by heating, preferably for about an hour in concentrated, strong acid, preferably 85% H₃PO₄.

Scheme F shows an alternative means for preparing the compounds of the present invention. Amino carboximides of the formula III in a suitable solvent, preferably a lower alkanol, are treated with an excess of an ester of the formula R¹CHQCO₂R, where R is lower alkyl and an excess of a base, preferably a metal lower alkoxide, preferably at the boiling point of the solvent to give compounds of the present invention. Many arylacetic esters are commercialy available or can be prepared in one step from commercially available arylacetic acids by esterification with an excess of an alcohol, ROH, preferably at reflux with ethyl or methyl alcohol, used as solvent in the presence of an acid catalyst such as H₂SO₄ or p-TsOH. Alternatively, a coupling reagent such as DCC can be used, preferably in a solvent such as CH₂Cl₂ with a catalylst such as DMAP. Phenylacetic acids may be prepared by acid or base hydrolysis of arylacetonitriles which in turn may be prepared by treatment of aryl halides with CN⁻, preferably in solvents such as DMF, MeOH, EtOH, water, DMSO, or mixtures thereof. Further examples of arylacetic esters may be prepared from aryl carboxylic acids under Arndt-Eistert (Meier and Zeller Angew. Chem. Int. Ed. Engl. 1975, 14, 32-43.) or related homologation conditions.

Aminoesters of the formula IV can be converted to compounds of the present invention by reaction with an excess of a nitrile of the formula R¹CHQCN and sodium. This reaction is preferably performed neat with heating.

Pyrazolo[3,4-d]pyrimidin-4-ones may be further elaborated as described below to give additional compounds of the present invention. Electrophilic aromatic substitution reactions can be performed on the R¹ aryl or heteroaryl group to introduce substituents. Such reactions include, but are not limited to nitration, acylation (Friedel-Crafts), halogenation, alkylation (Friedel-Crafts), chloromethylation, sulfonation, and aminomethylation (Mannich reaction). Conditions for performing these reactions are familiar to those skilled in the art of organic synthesis, generally involving reaction of the electrophile with the aryl or heteroaryl substrate in the presence of a catalyst. In the case of nitrations or Mannich reactions, the catalyst is preferably a protic acid which may serve as solvent, where the electrophile is generated in situ from saltpeter, or an amine and a carbonyl component, respectively. For other electrophilic aromatic substitution reactions, preferred catalysts are Lewis acids, including but not limited to FeX₃, AlX₃, and ZnX₂, where X is halogen.

The compounds prepared above which have an amino group can be derivatized by reaction with electrophiles including, but not limited to acyl halides, anhydrides, isocyanates, chloroformates, sulfonyl halides, alkyl halides, lactones, or esters. Conditions for performing these addition reactions are familiar to those skilled in the art of organic synthesis, generally involving addition of the electrophile to the nucleophile, preferably in solution at a temperature between 0° C. and RT. Addition of a base may be necessary. It should be noted that the products of these reactions can react further with some electrophiles at the pyrimidinone nitrogen (N5). The resulting functional groups (amides, carbamates, etc.) are less stable to basic hydrolysis than the desired anilino- or aliphatic groups and can be cleaved back to the pyrimidinone having H on N5. Reaction of compounds bearing an amine group with agents such as haloacyl halides, α,β-unsaturated acid halides, or halosulfonyl halides gives intermediates which can react with nucleophiles such as primary or secondary amines, diamines, alkoxides, aminoalcohols or thiols.

The compounds prepared above, which have a carboxyl group, can be derivatized by activation and reaction with nucleophiles including, but not limited to amines and alcohols to give, respectively, amides and esters. The coupling of amines and carboxylic acids with carbodiimides has been reviewed (Klausnew and Bodansky Synthesis, 1972, 453-463), and the variety of additional reagents available for effecting it as well as the potential need for protecting groups (Green and Wuts “Protective Groups in Organic Synthesis” Second Edition, John Wiley & Sons, 1991) to mask reactive functionality can be appreciated by those skilled in the art. The preparation of esters from acids has been described above. Reduction of these amides and esters to amines and alcohols can be performed using a suitable hydride reducing agent.

The compounds prepared above which have an amino group can be derivatized by conversion to an electrophilic species by activation with phosgene or a phosgene equivalent (Tetrahedron: Asymmetry 1995, 6, 745; J. Org. Chem. 1994, 59, 1937.), preferably in the presence of a base, and reaction with nucleophiles including, but not limited to amines, alcohols, and sulfonamides to give, respectively, ureas, carbamates, and sulfonylureas. Conditions for performing these reactions and the hazards associated with handling phosgene and phosgene equivalents are familiar to those skilled in the art of organic synthesis, and all appropriate precautions should be taken.

Further transformations which may be required to prepare compounds of the present invention include reductions of ketones, aldehydes, esters, acids, amides or reductive aminations by alumino- and borohydride reagents (J. Seyden-Penne “Reductions by the Alumino and Borohydrides in Organic Synthesis” VCH Publishers, Inc., 1991) and oxidations of groups including but not limited to alcohols, aldehydes, olefins, thioethers, sulfoxides, and heteroaryl groups (Milos Hudlicky “Oxidations in Organic Chemistry” American Chemical Society, 1990). Reduction of functional groups such as alkenes, alkynes, nitrogen, nitro- or cyano-groups could be accomplished by catalytic hydrogenation or by dissolving metal reduction. Further elaboration of intermediates containing electrophilic sites to compounds of the present invention could be accomplished by displacement with nucleophiles including, but not limited to, CN⁻, amines, alkoxides, mercaptans, or carbanions. Still other compounds of the present invention could be prepared by coupling of aryl halides, triflates, or stannames with the appropriate boronic acids (Stilk, J. K. Angew. Chem. Int. Ed. Engl. 1986, 25, 508; Suzuki, A. Pure Appl. Chem. 1985, 57, 1749.). The compounds prepared above, which have a carbonyl group, can be derivatized further by reaction with nucleophiles to give secondary alcohols. Such nucleophiles include, but are not limited to, Grignard reagents, alkyl-, alkenyl-, and alkynyl-lithium reagents, and allyl-stannanes, silanes, and the like. Compounds prepared as described above could be further elaborated by rearrangements such as the Beckmann (Gawley in Org. React. 1988, 35, 1-420.) or other rearrangements.

Further elaboration of the compounds prepared above can be accomplished by generation of an organomagnesium organolithium species by directed metallation (Beak and Meyers Acc. Chem. Res. 1986, 19, 356-363; Beak and Snieckus Acc. Chem. Res. 1982, 15, 306-312; Katritzky, Lam, and Sengupta Prog. Heterocycl. Chem. 1989, 1, 1-29) or from an aryl halide by lithium-halogen exchange (Parham and Bradsher, Acc. Chem. Res. 1982, 15, 300-305).

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “° C.” for degrees Celsius, “MS or mass spec.” for mass spectrum, “g” for gram or grams, “h” for hour or hours, “mg” for milligram or milligrams, “mL” for milliliter or milliliters, “mmol” for millimoles, “M” for molar, “min” for minute or minutes, “DMF” for dimethylformamide, “THF” for tetrahydrofuran, “Boc” for t-butoxycarbonyl, “Bop” for (benzotriazol-1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate, “EDC” for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, “BopCl” for bis(2-oxo-3-oxazolidinyl)phosphinic chloride, “ether” for diethyl ether, “aq” for aqueous, “RT” for ambient temperature, “HOAc” for acetic acid, “EtOAc” for ethyl acetate “p-TsOH” for para-toluenesulfonic acid, “DIEA” for N,N-diisopropylethylamine, “t-BuOH” for t-butanol, “EtOH” for ethanol, “MeOH” for methanol, “NBS” for N-bromosuccinimide, and “TFA” for trifluoroacetic acid. “Mass spec.” results refer to M/z for the product species composed entirely of the most prevalent isotopes of each of its constituent atoms, i.e. 12 for carbon, 1 for hydrogen, 35 for Cl, 14 for N, and 16 for O. Ionization techniques used give M⁺, (M+H )⁺, or (M−H)⁻ species. Proton (¹H) nuclear magnetic resonance (NMR) experiments were performed on dilute solutions in the solvent indicated at the frequency (generally 300 MHz) indicated. Chemical shifts are reported in ppm downfield from tetramethylsilane. The following abbreviations are used: “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, and “br.” for broad. Reported integrations are approximate. It is understood by those experienced in the interpretation of NMR spectra that some proton signals are absent, increased or diminished in measured intensity in a given spectrum due to factors such as poor instrument phase, rapid exchange with trace water or protons in the solvent, or because they resonate at a frequency outside that recorded (generally −0.2 to +15 ppm). It is also understood that chemical shifts for a given compound may vary due to factors such as concentation or pH of the sample. It is further understood that due to the precision in measurement of coupling constants, signals for coupled protons may have coupling constants that differ slightly.

Example 1 1-(2,4,6-Trichlorophenyl)-3-(methylthio)-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 176 mg (0.5 mmol) of 5-amino-3-(methylthio)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 220 mg (92%) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 245-248° C. Mass spec. Calc'd for C₂₀H₁₆N₄O₂SCl₃: 481.0060. Found: 481.0076 (M+H)⁺.

Example 2 1-(2,4,6-Trichlorophenyl)-3-(methylthio)-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 55 mg (0.11 mmol) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-methoxbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of CH₂Cl₂ was added 1 mL (1 mmol) of 1 M boron tribromide in CH₂Cl₂. The solution was stirred 35 min. at ambient temperature, and it was then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO₄), and concentrated under reduced pressure to afford 52 mg (98%) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, m.p. 264-266° C. Mass spec. Calc'd for C₁₉H₁₃N₄O₂SCl₃: 465.9825(M)⁺. Found: 465.9798.

Starting from 5-amino-3-(methylthio)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide, the following compounds were prepared by methods similiar to those used to synthesize the compounds above:

TABLE I

Ex. # R¹ m.p. (° C.) MS 3 phenyl 234-238 4 imidazol-4-yl 441 5 4-pyridyl 283-287 452 6 3,4-dimethoxyphenyl 226-230 511 7 3-nitrophenyl 243-255 496 8 4-methoxyphenyl 263-267 9 4-hydroxyphenyl 294-296 467 10 2,5-dimethoxyphenyl 137-150 481 11 2,5-dihydroxyphenyl 483 12 4-aminophenyl 466 13 3,4-methylenedioxyphenyl 257-260 14 2-thienyl 218-222 457

Example 15 1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred solution of 320 mg (1.9 mmol) of 2-cyano-3-ethoxypentenamide in 7 mL of MeOH was added 465 mg (2.2 mmol) of 2,4,6-trichlorophenylhydrazine. The solution was stirred 3 h at reflux, treated with 2 mL of water, and allowed to stir an additional 1 h, cooling to RT. The white solid which precipitated was filtered, washed with 2:1 MeOH-water, and air-dried to afford 520 mg (82%) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide, mp 186-188° C., Mass Spec (CI+): 331.9989 (M)⁺.

Part B: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-ethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 235-238° C. Mass Spec.: 463 (M+H)⁺.

Example 16 1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 80 mg (0.17 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH₂Cl₂ was added 1 mL (1 mmol) of 1 M boron tribromide in CH₂Cl₂. The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 tetrahydrofuran-EtOAc. The organic extract was washed with brine, dried (MgSO₄), and concentrated under reduced pressure to afford 77 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass Spec.: 449 (M+H)⁺.

Example 17 1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(4-(4-methoxyphenyl)benzyl))pyrazolo[3,4-d]pyrimidin-4-one

To a stirred mixture of 100 mg (0.2 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-bromobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 38 mg (0.25 mmol) of 4-methoxyphenylboronic acid in 10 mL of toluene, 0.5 mL of EtOH, and 2 mL of 2 M Na₂CO₃ was added to 5 mg of Pd(Ph₃P)₄. The mixture was heated to reflux overnight, poured into water, and extracted with CHCl₃. The organic extract was dried (MgSO₄), filtered through celite, chromatographed (elution with 5% MeOH/CH₂Cl₂), and recrystallized to afford 64 mg (59%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-(4-methoxyphenyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a pale brown powder, mp 275-277° C., Mass spec.: 537 (M−H)⁻.

Starting from 5-amino-3-ethyl-1-(2,4,6 trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the compounds above:

TABLE II

Ex. # R¹ m.p. (° C.) MS 18 3-indolyl 296-299 474 19 3-hydroxy-4-methylphenyl amorphous 20 3-methoxy-4-methylphenyl 263-265 21 4-hydroxy-3-methylphenyl 260-263 22 4-methoxy-3-methylphenyl 245-247 479 23 phenyl 240-241 431 24 3,4,5-trimethoxyphenyl 224-226 523 25 4-bromophenyl 296-299 511 26 4-hydroxy-3-nitrophenyl 263-266 27 2-methoxyphenyl 188-191 463 28 4-pyridyl 277-280 432 29 3-amino-2-methylphenyl 242-243 30 3,4-dimethoxyphenyl 220-222 493 31 3,4-dihydroxyphenyl 465 32 2-pyridyl HOAc 164-169 433.0255 33 4-hydroxy-3-methoxyphenyl 260-280 479 34 4-methoxyphenyl 261-262 463 35 4-hydroxyphenyl 289-291 449 36 3-hydroxy-4-methoxyphenyl 237-240 479 37 3-aminophenyl 236-240 447.0418 38 4-aminophenyl 256-259 448 39 3-methylphenyl 238-240 40 5-methoxy-3-indolyl 295-298 41 3-amino-4-hydroxyphenyl amorphous 464 42 3,4-dimethoxy-6-hydroxy- 203-205 methylphenyl 43 3-(dimethylaminomethyl)phenyl amorphous 492 HCl salt 44 4-amino-3-nitrophenyl amorphous 491 45 4-(dimethylamino)phenyl 476 46 3-(ethoxycarbonylmethyl)phenyl 168-169 517 47 3-(carboxymethyl)phenyl 192-194

Example 48 1-(2,4,6-Trichlorohenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred solution of 106 g (500 mmol) of 2,4,6-trichlorophenyl hydrazine in 600 mL of absolute ethanol was added 48.1 mL (530 mmol) of isobutyraldehyde. The solution was stirred 2 h at RT and concentrated under reduced pressure to afford an oil. The crude oil was dissolved in 450 mL of dry DMF and cooled to 0° C. This solution was treated with 94.3 g (530 mmol) of NBS in four portions over 10 min. The solution was stirred 1 h at 0° C. and poured onto ice. The mixture was diluted with water and extracted with 800 mL of ether. The organic extract was washed twice with water and once with brine, dried (MgSO₄), and concentrated under reduced pressure to afford an oil. In a separate flask, 44.3 g (670 mmol) of malononitrile in 140 mL of EtOH was cooled to 0° C. and treated with 252 mL (670 mmol) of 2.66 M NaOEt in EtOH over 6 min. This solution was added in four portions over 5 min. to a rapidly stirred solution of the crude bromohydrazone in 350 mL of absolute EtOH. Using a heat pistol, this solution was maintained at reflux for 10 min. further. The reaction was cooled, quenched with 5% aq. HOAc, and extracted twice with ether. The combined organic extracts were washed (brine), dried (MgSO₄) and filtered over activated charcoal and celite, and concentrated under reduced pressure. The product was chromatographed on silica gel (gradient elution with 1:3 ether-hexanes and 2:1 ether-CH₂Cl₂) to afford 93.5 g (57%) of 5-amino-4-cyano-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.51(s, 2H); 4.28(br. s, 2H); 3.05(septet, 1H, J=7.0 Hz); 1.36(d, 6H, J=7.0 Hz).

Part B: Thirty grams (91.0 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole was dissolved in 80 mL of con. H₂SO₄ and stirred 24 h at RT. The solution was added to cold aqueous NaOH, and the resulting precipitate was filtered, washed with water, and dried under vacuum to give 29.1 g (92%) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ 7.49(s, 2H); 5.06-5.63(m, 4 H); 3.06(septet, 1H, J=6.8 Hz); 1.39(d, 6H, J=6.9 Hz).

Part C: To a stirred solution of 167 mg (0.5 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 170 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 204-205° C., Mass Spec: 477 (M+H)⁺.

Example 49 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 65 mg (0.14 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of CH₂Cl₂ was added 1 mL (1 mmol) of 1 M boron tribromide in CH₂Cl₂. The solution was stirred 1 h at ambient temperature and then cooled to 0° C. The reaction was quenched with 4 mL of 1 M aq. HCl. The mixture was poured into water and extracted with 1:1 THF-EtOAc. The organic extract was washed with brine, dried (MgSO₄), and concentrated under reduced pressure to afford 63 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. ¹H NMR (300 MHz, DMSO) δ 12.46(br. s, 1H); 9.33(br. s, 1H); 7.96(s, 2H); 7.03(t, 1H, J=7.7 Hz); 6.55-7.08(m, 3H); 3.75(s, 2H); 3.19-3.36(m, 1H); 1.29(d, 6 H, J=7.0 Hz).

Starting from 5-amino-3-isopropyl-1-(2,4,6 trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the examples above:

TABLE III

Ex. # R¹ m.p. (° C.) MS 50 3-hydroxy-4-methoxyphenyl 491 51 3-aminophenyl 462 52 4-aminophenyl 223-225 462 53 4-methoxyphenyl 475 54 4-amino-3-methoxyphenyl 238-240 55 4-amino-3-hydroxyphenyl 210-217 (dec.) 476 56 4-(dimethylaminomethyl)phenyl 278-281 (dec.) HCl salt 57 5-methoxy-2-methylindol-3-yl 528 58 5-hydroxy-2-methylindol-3-yl 514 59 4-bromophenyl 229-230 60 2-pyridyl 214-215 448.0506 61 4-pyridyl 273-275 448.0502 62 4-methylphenyl 205-206 461.0696 63 2-methylphenyl 194-195 461.0700 64 3-pyridyl 214-215 448.0506 65 4-methyl-3-pyridyl 225-227 66 3-amino-2-methylphenyl 474 67 4-(methylamino)phenyl 244-246 476 68 2H-1,4-benzoxazin-3-on-7-yl 516 69 4-chloro-3-pyridyl 245-248 480

Example 70 1-(2,4,6-Trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 146 mg (0.42 mmol) of 5-amino-3-cyclopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 533 mg (2.53 mmol) of ethyl 3-hydroxy-4-methoxyphenylacetate followed by 1.91 mL (5.1 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 46 mg (22%) of 1-(2,4,6-trichlorophenyl)-3-cyclopropyl-6-(3-hydroxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass Spec.: 489 (M−H)⁻.

Starting from 5-amino-3-cyclopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the examples above:

TABLE IV

Ex. # R¹ m.p. (° C.) MS 71 Indazol-4-yl 483 72 Indazol-5-yl 274-283 483 73 Indazol-6-yl 483 74 4-Aminophenyl 460 75 Benzoxazol-2-on-5-yl 500 76 3-Hydroxy-4-nitrophenyl 259-260 506 77 4-(N,N-dimethylglycinamido)phenyl 250-253

Example 78 1-(2,4,6-Trichlorophenyl)-3-trifluoromethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 186 mg (0.50 mmol) of 5-amino-3-trifluoromethyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 555 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.26 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 23 h at reflux, and the heating mantle was then removed. The reaction was treated with 10 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:3 ether-hexanes. The off-white solid was briefly air-dried to give 230 mg (91%) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one. Mass spec.: 503 (M+H)⁺.

Example 79 1-(2,4,6-Trichlorophenyl)-3-trifluoromethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 60 mg (0.12 mmol) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of CH₂Cl₂ was added 2 mL of a 1M solution of BBr₃ in CH₂Cl₂. The solution was stirred 2.5 h at RT and quenched with 1 N aq. HCl. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO₄), and concentrated under reduced pressure. The crude product was chromatographed on silica gel (elution with 1:1 hexanes-THF, then THF) to afford 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, as an off-white solid. Mass spec.: 487 (M−H)⁻.

Starting from 5-amino-3-(trifluoromethyl)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide the following compounds were prepared by methods similiar to those used to synthesize the compounds above:

TABLE V

Ex. # R¹ m.p. (° C.) MS 80 3-aminophenyl 488 81 4-aminophenyl 488 82 4-methoxyphenyl 263-265 501 83 4-hydroxyphenyl 487 84 4-pyridyl 474 85 3-hydroxy-4-methoxyphenyl 517 86 4-hydroxy-3-methoxyphenyl 517

Example 87 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(3-(N,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred, cooled (0° C.) solution of 110 mg (0.23 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-amino-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 4 mL of THF was added 0.084 mL (0.6 mmol) of triethylamine followed by 0.024 mL (0.3 mmol) of chloroacetyl chloride. The solution was stirred 2 h, warming to ambient temperature. The reaction was quenched by dropwise addition of 5 mL of 0.5 N aq. HCl, and the resulting solid was collected by filtration. The product was washed with water then 1:1 ether-hexanes and air-dried to afford 96 mg (76%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(chloroacetamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 237-238° C. ¹H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 9.69(s, 1H); 7.93(s, 2H); 7.15(d, 1H, J=7.3 Hz); 7.07(t, 1H, J=7.7 Hz); 6.95(d, 1H, J=8.7 Hz); 4.25(s, 2H); 3.90(s, 2H); 3.20-3.33(m, 1H); 2.07(s, 3H); 1.30(d, 6H, J=6.9 Hz).

Part B: To a stirred solution of of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(chloroacetamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of THF was added 1 mL of 40% aq. dimethylamine. The solution was stirred overnight at ambient temperature and treated with water until a precipitate formed. The precipitate was filtered, washed with water and 1:1 ether-hexanes, and air-dried to afford 46 mg (75%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-(N,N-dimethylglycinamido)-2-methylbenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 219-222° C. Mass spec. (ESI−): 561((M−H)⁻).

By allowing m-substituted anilines to react with suitable acylating agents and performing further synthetic manipulations as necessary, the following compounds wherein R¹=phenyl were prepared by methods similiar to those used to synthesize the compounds above:

TABLE VI

Ex. R² R⁷ (meta) R⁷ (ortho) mp (° C.) MS 88 Et CH₃SO₂NH H 524 89 i-Pr CH₃SO₂NH H 538 90 i-Pr CF₂HCONH H 538 91 i-Pr CH₃CONH H 502 92 i-Pr CH₃NHCONH H 517 93 i-Pr HOCH₂CH₂NHCONH H 547 94 i-Pr HO(CH₂)₄NHCONH H 577 95 i-Pr (Fluorophen-4-yl)CH₂NHCONH H 613 96 i-Pr (Fluorophen-3-yl)CH₂NHCONH H 613 97 i-Pr Morpholin-4-ylCONH H 575 98 i-Pr PhCH₂N(CH₃)CONH H 609 99 i-Pr Tetrahydrofur-2-ylCH₂NHCONH H 585 100 i-Pr 4-hydroxypiperid-1-ylCONH H 589 101 i-Pr Pyrid-2-ylCH₂NHCONH H 596 102 i-Pr Pyrid-3-ylCH₂NHCONH H 596 103 i-Pr 4-Methylpiperazin-1-ylNHCONH H 603 104 i-Pr Pyrid-3-ylNHCONH H 582 105 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CONH H 590 106 Et (CH₃)₂NCH₂CONH Me 218-221 547 107 i-Pr (Methoxyphen-2-yl)CH₂NHCONH H 625 108 i-Pr (Methoxyphen-4-yl)CH₂NHCONH H 625 109 i-Pr 2-hydroxypiperid-1-ylCONH H 589 110 Et CH₃CONH H 488

Example 111 1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(4-methanesulfonylaminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 45 mg (0.1 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of ether-CH₂Cl₂ was added 0.5 mL of pyridine followed by 0.020 mL (0.26 mmol) of methanesulfonyl chloride. The solution was stirred 39 h at ambient temperature and poured into 1 N aq. HCl. The mixture was extracted with EtOAc, then hexanes. The combined organic extracts were washed with water then brine, dried (MgSO₄), and concentrated under reduced pressure to afford 52 mg of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(4-methanesulfonylaminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. Mass spec. (ESI+): 526 (M+H)⁺.

Example 112 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred, cooled (0° C.) solution of 9.26 g (20 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 45 mL of THF and 10 mL of DMF was added 3.90 mL (28 mmol) of triethylamine followed by 1.99 mL (25 mmol) of chloroacetyl chloride over 5 min. The solution was stirred 30 min. at 0° C. and quenched by addition of 150 mL of 0.1 N aq. HCl. The resulting solid was collected by filtration, washed with water then 1:1 ether-hexanes, and air-dried to afford 10.2 g (95%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid. ¹H NMR (300 MHz, DMSO) δ 12.49(s, 1H); 9.74(s, 1H); 7.97(s, 2H); 7.46(d, 2H, J=8.0 Hz); 7.20(d, 2H, J=8.8 Hz); 4.19(s, 2H); 3.80(s, 2H); 3.20-3.33(m, 1H); 1.28(d, 6H, J=6.9 Hz).

Part B: To a stirred solution of 300 mg (0.55 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(chloroacetamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 6 mL of 1:1 DMF-THF was added 1 g of piperazine. The solution was stirred overnight at ambient temperature and poured into water. The mixture was extracted twice with EtOAc, and the combined organic extracts were washed (brine), dried (MgSO₄), and concentrated under reduced pressure to afford 230 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(piperazin-1-ylmethylcarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. Mass spec. (ESI+): 588 ((M+H)⁺).

Example 113 (S)-1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 105 mg (0.22 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 235 mg (1.09 mmol) of Boc-L-proline in 2 mL of DMF was added 0.35 mL (2.5 mmol) of triethylamine followed by 490 mg (1.11 mmol) of Bop. The solution was stirred overnight at ambient temperature then poured into EtOAc. This solution was washed sequentally with 0.5 M HCl then dilute aq. Na₂CO₃ then brine, dried (MgSO₄), and concentrated under reduced pressure. The crude product was recrystallized from EtOAc-hexanes to afford 116 mg (80%) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid, mp 225-226° C., Mass spec.: 657 M−H⁻).

Example 114 (S)-1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(prolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Fifty mg (0.076 mmol) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(N-t-butoxycarbonylprolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one was dissolved in 2 mL of 4 M HCl, and the solution was stirred 1 h at RT. The solution was concentrated under reduced pressure to afford 45 mg (100%) of (S)-1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(prolinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. ¹H NMR (300 MHz, DMSO) δ 12.42(s, 1H); 10.67(s, 1H); 7.97(s, 2H); 7.49(d, 2H, J=8.5 Hz); 7.23(d, 2H, J=8.4 Hz); 4.27-4.31(m, 1H); 3.82(s, 2H); 3.18-3.34(m, 5H); 2.28-2.40(m, 1H); 1.84-1.95(m, 3H); 1.28(d, 6H, J=6.9 Hz).

Example 115 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(dimethylaminomethyl)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 464 mg (1.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 10 mL of glacial HOAc was added 0.4 mL of 37% aq. formaldehyde followed by 0.5 mL of 40% aq. dimethylamine. The solution was stirred overnight at RT, and it was then heated to just below reflux for 20 min. The solution was poured into water and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO₄), and chromatographed on silica gel (elution with EtOAc) to afford, after removal of solvent, 135 mg (26%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(dimethylaminomethyl)-3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white, amorphous solid. Mass spec. (ESI+): 520 (M+H)⁻.

Example 116 1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(3-pyridylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 167 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-ethyl-4-carboxamido-5-aminopyrazolo in 5 mL of ethanol was added 480 mg (3.0 mmol) of ethyl 3-pyridyl acetate followed by 1.13 mL (3.0 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 10 mL of 10% aq. HOAc. The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 210 mg (97%) of 1-(2,4,6-trichlorophenyl)-3-ethyl-6-(3-pyridylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 257-260° C. ¹H NMR (300 MHz, DMSO) δ 12.56(s, <1H (exchanges with solvent)); 8.46(d, 1H, J=1.5); 8.40(dd, 1H, J=4.8, 1.5 Hz); 7.96(s, 2H); 7.60-7.64(m, 1H); 7.25-7.30(m, 1H); 3.90(s, 2H); 2.83(q, 2H, J=7.3 Hz); 1.23(t, 3H, J=7.5 Hz).

Example 117 (+/−)-1-(2,4,6-Trichlorophenyl)-3-ethyl-6-(α-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 167 mg (0.50 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-4-carboxamido-5-aminopyrazole in 6 mL of ethanol was added 544 mg (3.0 mmol) of (+/−) ethyl mandelate followed by 1.13 mL (3.0 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 10 mL of 10% aq. HOAc. The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 210 mg (94%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(α-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 246-248° C. Mass spec. (ESI−): 449 (M−H)⁻.

Example 118 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.14 mL (1.0 mmol) of Et₃N in 4 mL of THF was added 0.063 mL (0.6 mmol) of 2-chloroethanesulfonyl chloride. The solution was stirred 1 h, warming to ambient temperature. The solution was poured into 10% aq. citric acid and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO₄), and concentrated under reduced pressure. The crude product was chromatographed (elution with 1:1 EtOAc-hexanes) to afford 221 mg (80%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid. ¹H NMR (300 MHz, DMSO) δ 12.47(br. s, 1H); 9.92(br. s, 1H); 7.97(s, 2H); 7.17(d, 2H, J=8.4 Hz); 7.02(d, 2H, J=8.4 Hz); 6.69(dd, 1H, J=16.5, 9.9 Hz); 6.04(d, 1H, J=16.5 Hz); 5.96(d, 1H, J=9.9 Hz); 3.78(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).

Example 119 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethanesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, solution of 23 mg (0.042 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of THF was added 1 mL of 2M diethylamine in THF. The solution was stirred 3 h and concentrated under reduced pressure. The product was dissolved in 1 mL of benzene and 0.05 mL of MeOH, frozen, and lyophilized to afford 25 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethenesulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous white solid. ¹H NMR (300 MHz, DMSO) δ 7.96(s, 2H); 7.19(d, 2H, J=8.5 Hz); 7.08(d, 2H, J=8.8 Hz); 3.79(s, 2H); 3.18-3.32(m, 1H); 3.13(t, 2H, J=7.5 Hz); 2.53(t, 2H, J=7.5 Hz); 1.99(s, 6H); 1.28(d, 6H, J=7.0 Hz).

Example 120 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 347 mg (1.0 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 777 mg (4.0 mmol) of ethyl 4-(hydroxymethyl)phenylacetate followed by 2.0 mL (5.33 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 25 mL of 5% aq. HOAc, cooled to ambient temperature, and extracted with EtOAc. The organic extract was washed twice with water and once with brine, dried (MgSO₄), and chromatographed on silica gel (elution with 1:1 EtOAc-hexanes) to give, after removal of solvent, 320 mg (67%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(hydroxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. ¹H NMR (300 MHz, CDCl₃) d 11.46(br. s, 1H); 7.54(s, 2H); 7.42(d, 2H, J=8.1 Hz); 7.31(d, 2H, J=8.5 Hz); 4.66(s, 2H); 4.00(s, 2H); 3.47(septet, 1H, J=7.0 Hz); 1.48(d, 6H, J=7.0 Hz).

Example 121 (+/−)-1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(1,4-dimethyliperazine-2-ylcarboxamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred, cooled (0° C.) solution of 463 mg (1.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.28 mL (2.0 mmol) of Et₃N in 8 mL of THF was added 0.131 mL (1.2 mmol) of 2,3-dichloropropanoyl chloride. The solution was stirred 0.5 h, warming to ambient temperature. The solution was quenched with water and filtered. The solid was washed with 0.1 N aq. HCl, then water, then 1:1 hexanes-ether. The product was air-dried briefly to afford 390 mg (71%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-chloroacrylamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. ¹H NMR (300 MHz, DMSO) δ 12.49(br. s, 1H); 10.14(br. s, 1H); 7.97(s, 2H); 7.53(d, 2H, J=8.4 Hz); 7.22(d, 2H, J=8.4 Hz); 6.36(d, 1H, J=2.6 Hz); 6.03(d, 1H, J=2.5 Hz); 3.82(s, 2H); 3.18-3.32(m, 1H); 1.28(d, 6H, J=7.0 Hz).

Part B: To a stirred, solution of 112 mg (0.2 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-cloroacrylamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of THF was added 0.5 mL of N,N′-dimethylethylene diamine. The solution was stirred overnight, poured into water, and extracted with EtOAc. The organic extract was washed (brine), dried (MgSO₄), and concentrated under reduced pressure to afford 102 mg (84%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(1,4-dimethylpiperazine-2-ylcarboxamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous white solid. Mass spec. (ESI+): 602.1608 (M+H)⁺.

Example 122 1-(2,6-Dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

The amino carboxamide, 5-amino-3-isopropyl-1-(2,6-dichlorophenyl)pyrazole-4-carboxamide (0.30 g, 0.96 mmol), p-diethyl phenylenediacetate (8 eq, 1.92 g, 7.66 mmol) and sodium ethoxide (21% in ethanol, 8 eq, 2.90 mL, 7.66 mmol) were refluxed overnight in ethanol (20 mL). The reaction was cooled and 10% aq HOAc was added. The mixture was extracted with EtOAc, washed with water and brine, dried over MgSO₄ and evaporated to dryness. The oily solid was purified by silica gel column chromatography with 1:1 hexane/ether as the eluent. The product, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (0.44 g, 93% yield), was recovered as a white solid, mp 168-169° C. Mass Spec.: 499 (M+H)⁺.

Example 123 1-(2,6-Dichlorophenyl)-3-isopropyl-6-(4-(carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

The ester, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.20 g, 2.4 mmol) was stirred at RT overnight with THF (50 mL), water (15 mL) and 1 N lithium hydroxide (7.20 mL). The solution was evaporated to near dryness, diluted with 1 N hydrochloric acid, vigorously stirred and the solid was collected by filtration and dried under high vacuum to give 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.01 g, 89% yield) as a white solid, mp 212-214° C. Mass Spec.: 471 (M+H)⁺.

Example 124 1-(2,6-Dichlorophenyl)-3-isopropyl-6-(4-(2-(N,N-dimethylamino)ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

The acid, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (0.100 g, 0.21 mmol) and N,N-dimethyethylenediamine (5 eq, 0.12 mL, 1.06 mmol) were suspended in DMF (3 mL). DIEA (5 eq, 0.18 mL, 1.06 mmol) was added and the suspension was stirred at RT for ten minutes. BOP (1.5 eq, 0.141 g, 0.32 mmol) was added and the reaction was stirred at RT overnight. The suspension was diluted with water, extracted with EtOAc, washed with water and brine, dried over MgSO₄ and evaporated to dryness. The oily residue was crystallized from a mixture of EtOAc, hexane and ether to give 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(2-(N,N-dimethylamino)ethylaminocarbonylmethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (0.039 g, 34% yield) as a white solid, mp 170-172° C. Mass Spec.: 541 (M+H)⁺.

Example 125 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(morpholine-4-yl)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

A flask equipped with a reflux condensor was flame-dried in vacuo and a nitrogen atmosphere was introduced. The flask was charged with triphosgene (1.37 g, 4.62 mmol). The reagent was dissolved in dry 1,2-dichloroethane (25 mL), and triethylamine (0.64 mL, 4.62 mmol) was added. The reaction was cooled to −30° C., and 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.1 g, 2.38 mmol) was added. Stirring was continued for 10 minutes and the reaction was the warmed to reflux. After heating for one hour, the reaction was cooled, diluted with methylene chloride, and washed sequentially with water and brine. The organic phase was dried over magnesium sulfate, filtered and evaporated to give the isocyanate (1.2 g). This material was of sufficient quality for the subsequent transformations.

The isocyanate (75.5 mg, 0.155 mmol) was dissolved in dry methylene chloride (2.0 mL) under a nitrogen atmosphere. 4-(2-aminoethyl)morpholine (30 μΛ, 0.232 mmol) was added, and stirring was continued for 1 hour. The precipitate was filtered and rinsed with three portions of methylene chloride and dried in vacuo to give 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-(morphline-4-yl)ethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (68 mg, 0.110 mmol, 71%). Mass spec. (ESI+) 618 (M+H)⁺.

Example 126 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Alternatively, the ureas may be prepared by the following procedure, which is suitable for parallel synthesis. The isocyanate (74 mg, 0.152 mmol) was dissolved in dry methylene chloride (3.0 mL) under a nitrogen atmosphere. Ethanolamine (14 μΛ, 0.227 mmol) was added and stirring continued for 15 minutes. Methanol (1.0 mL) was added to generate a homogeneous solution. The acidic ion exchange resin AG 50W-X8 (158 mg) was added. The reaction was then filtered and the solvents removed by evaporation. The product 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(2-hydroxyethylaminocarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one was obtained in excellent yield (78 mg, 93%). Mass spec. (ESI−) 547 (M−H)⁻.

Example 127 1-(2-Chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred suspension of 14.2 g (100 mmol) of 2-chloro-6-methylaniline in 40 mL conc. HCl at 0° C. was added a solution of 6.9 g (100 mmol) of sodium nitrite in 40 mL water dropwise via addition funnel. After stirring one hour at 0° C. a solution of 67.6 g (300 mmol) tin(II) chloride dihydrate in 70 mL conc. HCl was added dropwise via addition funnel. The reaction was sealed and placed in the refrigerator for 24 h. The mixture was filtered and the solid was washed with brine and then petroleum ether. The solid was taken up in 250 mL of 2 N NaOH, stirred 10 min. and filtered. This solid was dissolved in 100 mL diethyl ether and acidified with 4 N HCl in dioxane. The solid was collected by suction filtration, washed with diethyl ether and dried to afford 10.25 g (53%) of 2-chloro-6-methylhydrazine hydrochloride, mp 220-222 (dec)° C. Mass Spec (CI+): 157 (M+H)⁺.

Part B: To a stirred suspension of 3.0 g (15.5 mmol) of 2-chloro-6-methylhydrazine hydrochloride in 20 mL ethanol was added 2.2 mL (15.5 mmol) of triethylamine followed after 10 min by 1.5 mL (16.5 mmol) of isobutyraldehyde. The solution was stirred at room temperature for 2 h, poured into water and extracted with diethyl ether. The organic extract was washed with brine, dried (MgSO₄), and concentrated under reduced pressure to give 2.95 g (90%) of the imine intermediate as a liquid. The imine was taken up in 15 mL dimethylformamide, cooled to 0° C., and 2.99 g (16.8 mmol) of N-bromosuccinimide was added in small portions. After stirring at 0° C. for 30 min the reaction was diluted with diethyl ether and water. The layers were separated and the aqueous phase with extracted with diethyl ether. The organic extracts were combined, washed with water and brine, dried (MgSO₄) and concentrated under reduced pressure to give the bromohydrazone intermediate.

To a stirred solution of the bromohydrazone in 25 mL ethanol was added an ice cold solution of the anion of malononitrile prepared by adding 10.4 mL (28 mmol) of sodium ethoxide to 1.82 g (28 mmol) of malononitrile in 25 mL ethanol at 0° C. The mixture was heated to reflux for 30 min and then concentrated to one third the volume under reduced pressure. This solution was treated with 10% glacial acetic acid, diluted with water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO₄), and concentrated under reduced pressure. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluant afforded 1.82 g (47%) of 5-amino-4-cyano-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole, mp 116-118° C. Mass Spec. (CI+): 275 (M+H)⁺.

Part C: A mixture of 1.5 g (5.5 mmol) of 5-amino-4-cyano-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole in 5 mL conc. H₂SO₄ was stirred at room temperature for 24 hours. The reaction was slowly quenched with ice and then diluted with water. The solution was made basic with saturated Na₂CO₃, stirred 2 h and filtered. The solid was recrystallized from hexanes/EtOAc to afford 847 mg (53%) of 5-amino-3-isopropyl-1-(2-chloro-6-methylphenyl)pyrazole-4-carboxamide, mp 72-74° C. Mass Spec. (ES−): 291 (M−H)⁻.

Part D: To a stirred solution of 1.4 g (4.8 mmol) 5-amino-3-isopropyl-1-(2-chloro-6-methyl-phenyl)pyrazole-4-carboxamide in 100 mL absolute ethanol was added 5.14 g (28.8 mmol) of 4-amino-phenylacetate followed by 10.7 mL (28.8 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux and the heating mantle was then removed. The reaction was treated with water and 10% aq. HOAc, cooled to ambient temperature, and filtered. The solid purified by column chromatography on silica gel using 1:1 hexanes-EtOAc as eluant to afford 743 mg (38%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)-pyrazolo[3,4-d]pyrimidin-4-one, mp 206-207° C. Mass Spec. (CI+): 408 (M+H)⁺.

Example 128 1-(2-Chloro-6-methylphenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one Hydrochloride Salt

To a stirred solution of 500 mg (1.22 mmol) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 10 mL dry CH₂Cl₂ was added 0.85 mL (6.1 mmol) triethylamine followed by 632 mg (6.1 mmol) N,N-dimethylglycine and then 1.17 g (6.1 mmol) of 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). The reaction was stirred for 18 h at ambient temperature and then transferred directly to a flash column of silica gel and eluted with 5% MeOH in CH₂Cl₂. The isolated solid was dissolved in 20 mL dioxane and 1.1 mL of 4 N HCl in dioxane was added. The solid was collected by suction filtration and dried to give 490 mg (76%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-(N,N-dimethylglycinamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one hydrochloride salt, mp 297-299° C.

Example 129 1-(2,6-Dichloro-4-methylcarboxamidophenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred suspension of 4.33 g (18.5 mmol) of ethyl 4-amino-3,5-dichlorobenzoate in 8 mL conc. HCl at 0° C. was added a solution of 1.28 g (18.5 mmol) of sodium nitrite in 8 mL water dropwise. After stirring at 0° C. for 45 min, a solution of 12.52 g (55.5 mmol) tin(II) chloride in 14 mL conc. HCl was added dropwise. The reaction was sealed and placed in the refrigerator for 18 h. The solid was collected by suction filtration, washed with brine and then 2:1 petroleum ether-diethyl ether, treated with 1 N NaOH, and filtered. This solid was dissolved in diethyl ether, acidified with 4 N HCl in dioxane, filtered and washed with diethyl ether to give 2.85 g (54%) of ethyl 3,5-dichloro-4-hydrazinobenzoate hydrochloride, mp 225-227 (dec)° C. Mass Spec.: (CI+) 249 (M+).

Part B: A mixture of 2.5 g (8.75 mmol) ethyl 3,5-dichloro-4-hydrazinobenzoate hydrochloride, 1.1 g (7.3 mmol) 1-(ethoxypropylidine)malononitrile and 1.22 mL (8.75 mmol) triethylamine in 100 mL of ethanol was stirred at reflux for 66 h. The reaction was taken to one-third the volume via rotary evaportation under reduced pressure and the remaining solution was treated with water, stirred 30 min and filtered. Recrystallization from hexanes/EtOAc gave 1.16 g (45%) of 5-amino-4-cyano-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole, mp 173-175° C. Mass Spec.: (CI+) 353 (M+).

Part C: A solution of 1.64 g (4.64 mmol) of 5-amino-4-cyano-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)-pyrazole in 8 mL conc. H₂SO₄ was stirred at room temperature for 4 hours. The reaction was quenched carefully with ice and diluted with water. The solid was collected by suction filtration, washed with water and dried to give 1.26 g (73%) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide, mp 194-196° C. Mass Spec.: (CI+) 371 (M+).

Part D: To a stirred solution of 500 mg (1.35 mmol) of 5-amino-3-ethyl-1-(2,6-dichloro-4-carboethoxyphenyl)pyrazole-4-carboxamide in 10 mL ethanol was added 1.45 g (8.1 mmol) of methyl 4-methoxyphenylacetate followed by 2.6 mL (8.1 mmol) of 2.66 M sodium ethoxide in ethanol. The reaction was heated at relux for 18 h and then 10% aq. HOAc was added. After stirring an additional hour at relux, the heat was removed and the reaction solution was poured into ice water, stirred 10 min. and filtered. The solid was washed with water and diethyl ether and dried to give 480 mg (75%) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 277° C. Mass Spec.: (ES−) 471 (M−H)⁻.

Part E: To a stirred solution of 100 mg (0.21 mmol) of 1-(2,6-dichloro-4-carboxyphenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one was added 0.3 mL (2.1 mmol) of triethylamine followed by 71 mg (1.05 mmol) of methylamine hydrochloride and then 202 mg (1.05 mmol) of EDC. The reaction was stirred at ambient temperature for 18 h, transferred directly to a flash column of silica gel and eluted with 5% MeOH in CH₂Cl₂ to give 14 mg (14%) of 1-(2,6-dichloro-4-(methylcarboxamido)phenyl)-3-ethyl-6-(4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, mp 280-282° C. Mass Spec.: (CI+) 486 (M+).

Example 130 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(t-butoxycarbonylaminosulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled solution of 0.11 mL (1.26 mmol) of chlorosulfonyl isocyanate in 5 mL of CH₂Cl₂ was added 0.13 mL of t-BuOH. The solution was stirred 10 min. and added to a stirred, cooled (0° C.) solution of 231 mg (0.5 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-aminobenzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.2 mL (1.4 mmol) of Et₃N in 5 mL of CH₂Cl₂. The solution was stirred 1 h warming to ambient temperature, and it was then poured into 1 N aq. HCl. The mixture was extracted with EtOAc, and the organic extract was washed (brine), dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel (elution with 1:1 EtOAc-hexanes, then EtOAc) to afford 250 mg (78%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(t-butoxycarbonylaminosulfonamido)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid. ¹H NMR (300 MHz, DMSO) δ 12.44(s, 1H); 11.12(br. s, 1H); 9.70(br. s, 1H); 7.97(s, 2H); 7.21(d, 2H, J=8.4 Hz); 7.02(d, 2H, J=8.4 Hz); 3.78(s, 2H); 3.19-3.30(m, 1H); 1.27(d, 6H, J=6.9 Hz); 1.21(s, 9H).

Example 131 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 139 mg (0.40 mmol) of 5-amino-3-isopropyl-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 3 mL of absolute ethanol was added 329 mg (1.50 mmol) of ethyl 3-aminoindazol-5-ylacetate followed by 1.13 mL (3.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 16 h at reflux, and the heating mantle was then removed. The reaction was treated with 8 mL of 10% aq. HOAc, poured into water, and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO₄), concentrated under reduced pressure, and chromatographed on silica gel (gradient elution with 5% to 10% MeOH—CH₂Cl₂) to give, after removal of solvent, 123 mg (61%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(3-aminoindazol-5-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as a white, amorphous solid. Mass spec.: 502.0712 (M+H)⁺.

Example 132 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(benzoxazol-2-on-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (0° C.) solution of 309 mg (0.063 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-amino-3-hydroxybenz)pyrazolo[3,4-d]pyrimidin-4-one in 1 mL of THF was added 0.13 mL (1.0 mmol) of triethylamine followed by 0.05 mL (0.095 mmol) of 1.93 M phosgene in toluene. The solution was stirred 15 min., treated with 4 mL of 0.1 N aq. NaOH, and stirred 64 h at RT. The reaction was poured into 1 N aq. HCl and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO₄ plus activated charcoal and celite), and concentrated under reduced pressure to afford 26 mg (81%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(benzoxazol-2-on-6-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an amorphous solid. ¹H NMR (300 MHz, DMSO) δ 12.48(s, 1H); 11.57(br. s, 1H); 7.98(s, 2H); 7.03(dd, 1H, J=8.1, 1.4 Hz); 6.97(d, 1H, J=8.1 Hz); 3.84(s, 2H); 3.19-3.30(m, 1H); 1.28(d, 6H, J=7.0 Hz).

Example 133 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethoxycarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (−78° C.) solution of 0.10 mL (1.0 mmol) of N,N-dimethylethanolamine in 1 mL of THF was added 0.56 mL (0.90 mmol) of 1.6 M n-BuLi in hexanes over 2 min. The solution was stirred 5 min. at −78° C. and treated with 49 mg (0.10 mmol) of the isocyanate prepared in Example 107 above. The mixture was stirred 10 min., becoming homogeneous as it warmed to 0° C. The reaction was diluted with 5% aq. HOAc, then made slightly basic with saturated aq. NaHCO₃. The mixture was extracted with EtOAc, and the organic extract was washed (brine), dried (MgSO₄), and concentrated under reduced pressure to afford 43 mg(74%) of 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(2-(dimethylamino)ethoxycarbonylamino)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as a white solid, mp. 218-220° C. Mass spec: 577 (M+H)⁺.

Example 134 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred solution of 1.74 g (5.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-4-carboxamido-5-aminopyrazole in 30 mL of ethanol was added 2.9 mL (20 mmol) of methyl 1-methyl-2-pyrroleacetate followed by 7.50 mL (20 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 40 mL of 10% aq. HOAc. The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 2.07 g (92%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 219-221° C. Mass spec. (ESI+): 450 (M+H)⁺.

Example 135 1-(3-Formyl-2,4,6-trichlorophenyl)-3-isoproyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one

To a stirred, cooled (−60° C.) solution of 902 mg (2.0 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one in 10 mL of THF was added 2.56 mL (4.1 mmol) of 1.6 M n-BuLi in hexanes over 2 min. The solution was stirred 10 min. at −60° C. and treated with 1 mL DMF. The reaction solidified and was broken up by stirring, shaking, and warming to ambient temperature. The reaction was quenched with deuteromethanol then aq. HOAc. The mixture was extracted with EtOAc, and the organic extraxt was washed (brine), dried (MgSO₄), and concentrated under reduced pressure. The crude product was re-crystallized from EtOAc-hexanes to afford 560 mg (60%) of 1-(3-formyl-2,4,6-trichlorophenyl)-3-isopropyl-6-(1-methylpyrroy-2-ylmethyl)pyrazolo[3,4-d]pyrimidin-4-one as an orange solid. Mass spec. (ESI−): 450 (M−H)⁻.

Example 136 1-(2,4,6-Trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one

Part A: To a stirred solution of 7.5 g(153 mmol) sodium cyanide in 75 mL of THF was added 40 mL of DMF followed by 11.5 g (50.2 mmol) of of methyl 4-(bromomethyl)benzoate in 30 mL of DMF over 10 min. The solution was stirred 18 and treated with 100 mL water. The mixture was filtered, rinsed with water, and air-dried briefly to give 6.7 g (76%) of 4-(carbomethoxy)phenylacetonitrile as a white solid. ¹H NMR (300 MHz, DMSO) δ 7.95(d, 2H, J=8.4 Hz); 7.47(d, 2H, J=8.5 Hz); 4.14(s, 2H); 3.82(s, 3H).

Part B: The above nitrile ester was stirred with 120 mL of 6 N aq. HCl for 18 h at reflux and then cooled. The mixture was diluted with 160 mL water and then filtered. The white solid was rinsed with water, air-dried briefly, and placed in a vacuum oven at 75° C. for 1 h. This affords 6.89 g (100%) of 4-(carboxy)phenylacetic acid. ¹H NMR (300 MHz, DMSO) δ 7.92(d, 2H, J=8.5 Hz); 7.49(d, 2H, J=8.4 Hz); 3.63 (s, 2H).

Part C: To a stirred solution of 2.0 g (11.1 mmol) of 4-(carboxy)phenylacetic acid in 28 mL of absolute ethanol was added 0.5 mL of conc. Sulfuric acid. The solution was stirred 2 h at reflux and then cooled. The reaction was made basic with sodium carbonate and extracted with ether. The organic extract was washed (brine), dried (MgSO₄), and concentrated under reduced pressure to afford 2.3 g (88%) of ethyl 4-(carbethoxy)phenylacetate as an oil. ¹H NMR (300 MHz, CDCl₃) δ 8.01(d, 2H, J=8.4 Hz); 7.36(d, 2H, J=8.1 Hz); 4.37(q, 2H, J=7.1 Hz); 4.16(q, 2H, J=7.2 Hz); 1.39(t, 3H, J=7.2 Hz); 1.25(t, 3H, J=7.2 Hz).

Part D: To a stirred solution of 174 mg (0.50 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-4-carboxamido-5-aminopyrazole in 6 mL of ethanol was added 473 mg (2.0 mmol) of ethyl 4-(carbethoxy)phenylacetate followed by 0.94 mL (2.5 mmol) of 2.66 M NaOEt in ethanol. The solution was stirred overnight at reflux, and the product was precipitated by treatment with 8 mL of 10% aq. HOAc then 2 mL of saturated aq. NaHCO₃. The mixture was filtered, and the product was washed with 1:1 MeOH-water then 1:1 ether-hexanes and air dried to afford 232 mg (89%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carbethoxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one as an off-white solid, mp 233-235° C. Mass spec. (ESI+): 519.0754 (M+H)⁺.

Part E: To a stirred solution of 130 mg (0.250 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carbethoxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of THF was added 42 mg (1.0 mmol) of lithium hydroxide hydrate in 2 mL of water followed by 0.25 mL of methanol. The solution was stirred 3.5 h at RT and 10 min. at reflux. The reaction was diluted with ether, and washed twice with 0.1 N aq. NaOH. The combined aq. washings were acidified, and the resulting mixture was extracted with chloroform, then EtOAc. The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure to afford 123 mg (100%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carboxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-on as a white solid, mp. 294-295° C.

Part F: To a stirred solution of 49 mg (0.10 mmol) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(carboxy)benzyl)pyrazolo[3,4-d]pyrimidin-4-one and 0.06 mL (0.5 mmol) of 1-amino-4-methylpiperazine in 1 mL of DMF was added 0.052 mL of DIEA followed by 48 mg (0.15 mmol) of TBTU. The solution was stirred 16 h at 45° C., cooled to RT, and poured into water. The mixture was extracted with EtOAc, and the organic extract was concentrated under reduced pressure. Chromatography with 4:1 chloroform-MeOH afforded 34 mg (58%) of 1-(2,4,6-trichlorophenyl)-3-isopropyl-6-(4-(4-methylpiperazin-1-ylaminocarbonyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-on as a white solid. Mass spec: (ESI+) 588 (M +H)⁺.

Example 137 1-(4-(Acetamidophenyl-3-yl)-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

A solution of 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (200 mg, 0.383 mmol) and 3-acetamidobenzeneboronic acid (82 mg, 0.458 mmol) in a 25% solution of ethanol in toluene was stirred at RT under nitrogen for 30 min. Sodium carbonate solution (0.38 mL of a 2N solution, 0.766 mmol) was added followed by tetrabutylammonium bromide (6.1 mg, 0.019 mmol) and tetrakis(triphenylphosphine)palladium(0) (2 mg, catalytic). The reaction was stirred at reflux overnight, cooled to RT, filtered through Celite, washed with EtOAc, and concentrated. Purification by column chromatography using 1:1 hexanes-EtOAc as eluent afforded 114 mg (52%) of the title as a white solid, mp 224-225° C. Mass Spec: 576 (M+H)⁺.

Example 138 1-(2,6-Dichloro-4-formylphenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one

A two-neck flask was flame-dried, charged with 1-(4-bromo-2,6-dichlorophenyl)-3-isopropyl-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one (250 mg, 0.48 mmol) and 4 mL of THF, and placed under an argon atmosphere. The solution was cooled to 0° C. and isopropylmagnesium chloride (0.26 mL, 0.523 mmol) was added dropwise via syringe. The reaction was stirred at −78° C. for 2 min and DMF (0.08 mL, 1.06 mmol) was added via syringe. The reaction was stirred at −78° C. for 15 min and at RT for 30 min. The reaction was quenched with 10% aq. citric acid and extracted with EtOAc. The organic extract was washed with water then brine, dried (MgSO₄), and evaporated. Purification by column chromatography on silica gel using 2:1 hexanes-EtOAc as eluent afforded 68 mg (30%) of the title as a white solid, mp 212-214° C. Mass Spec: 469 (M−H)⁻.

Starting from the appropriate 3-substituted 5-amino-1-arylpyrazole-4-carboxamides the following compounds were prepared by methods similiar to those used to synthesize compounds in the examples and tables above:

TABLE VII

Ex# Y R² R¹ mp. (° C.) MS 139 Cl Et 4-Methoxyphenyl amorphous 393 140 Cl Et 4-Hydroxyphenyl amorphous 379 141 Cl Et 3-Methoxyphenyl amorphous 393 142 Cl Et 3-Hydroxyphenyl amorphous 379 143 Cl i-Pr 3-Hydroxyphenyl 227-228 395 144 Cl i-Pr 4-Aminophenyl amorphous 394 145 Cl i-Pr 3-Methoxyphenyl 407 146 Cl i-Pr 4-Methoxyphenyl amorphous 407 147 Cl i-Pr 4-Hydroxyphenyl amorphous 395 148 Cl Et 4-(N,N-dimethyl- 479 glycinamido)phenylHCl 149 Cl SCH₃ 4-Hydroxyphenyl 243-244 397 150 Cl SCH₃ 4-Methoxyphenyl 227-228 413 151 Br Et 3-Methoxyphenyl 178-180 439 152 Br Et 4-Aminophenyl 246-249 424 153 Br Et 3-Hydroxyphenyl 199-201 425 154 F Et 3-Methoxyphenyl 193-194 379 155 F Et 3-Hydroxyphenyl 235-237 365 156 Br Et 4-(N,N-dimethyl- 156-158 509 glycinamido)phenyl 157 F Et 4-Aminophenyl 231-233 364

TABLE VIII

Ex R⁶ R⁷ mp. (° C.) MS 158 H CH₃NHCH₂CH₂N(CH₃)COCH₂ 154-155 541 159 H H₂NCH₂CH₂NHCOCH₂ 140-142 513 160 H Piperazin-1-ylCOCH₂ 181-183 539 161 H CH₃CH₂NHCOCH₂ 242-244 496 162 H CH₃NHCOCH₂ 249-250 482 163 H 1-CH₃-piperazin-4-ylCOCH₂ 236-237 553 164 H (CH₃)₂NCH₂CH₂N(CH₃)COCH₂ 134-136 555 165 Cl 4-CH₃-piperazin-1-ylCOCH₂ 205-207 587

TABLE IX

Ex# R⁵ R⁶ R² R¹ mp. (° C.) MS 166 Cl CF₃ Et 3-Methoxyphenyl 192-193 497 167 Cl CF₃ Et 4-Aminophenyl 235-236 495 168 Cl CF₃ Et 4-Methoxyphenyl 240-241 497 169 Cl Br Et 4-Hydroxyphenyl 284-286 493 170 Cl Br Et 3-Hydroxyphenyl 242-244 495 171 Cl H Et 4-Hydroxyphenyl 262-263 413 172 Cl H Et 4-Aminoxyphenyl 159-161 414 173 Cl H Et 3-Hydroxyphenyl 242-244 413 174 Cl Br Et 3-Methoxyphenyl 232-233 507 175 Cl Br Et 4-Methoxyphenyl 252-253 507 176 Cl H Et 4-Methoxyphenyl 220-222 427 177 Cl H Et 3-Methoxyphenyl 186-187 427 178 F H SCH₃ 4-Hydroxyphenyl 267-268 415 179 F H SCH₃ 3-Hydroxyphenyl 252-253 415 180 Cl Br SCH₃ 4-Hydroxyphenyl 255-256 511 181 F H SCH₃ 4-Methoxyphenyl 193-194 429 182 F H SCH₃ 3-Methoxyphenyl 244-245 431 183 Cl Br SCH₃ 4-Methoxyphenyl 267-268 524 184 Me H Et 4-Hydroxyphenyl 255-256 395 185 Me Cl SCH₃ 4-Methoxyphenyl 252-255 459 186 Me H SCH₃ 4-Methoxyphenyl 233-235 425 187 Me Cl Et 4-Methoxyphenyl 245-246 441 188 Me Cl SCH₃ 4-Hydroxyphenyl 277-279 445 189 Me Cl Et 4-Hydroxyphenyl amorphous 429 190 Me H SCH₃ 4-Hydroxyphenyl 264-266 413 191 Me H Et 4-Methoxyphenyl 220-221 409 192 Me H Et 4-Hydroxyphenyl 257-259 395 193 Me H Et 3-Methoxyphenyl 188-190 409 194 Me H Et 4-Hydroxyphenyl 255-256 395 195 Cl CO₂H Et 4-Methoxyphenyl 292-294 196 Cl CO₂H Et 4-Hydroxyphenyl 308-310 457 197 Cl CO₂H Et 3-Methoxyphenyl amorphous 471 198 Cl CO₂H Et 3-Hydroxyphenyl 280-282 199 Me H i-Pr 4-Aminophenyl 205-206 408 200 Me H i-Pr 4-(N,N-Dimethylglycin 277-279 491 amido)phenyl 201 Cl CONHMe Et 4-Methoxyphenyl 278-280 486 202 Me H Et 4-Methoxyphenyl 220-221 409 203 Me H Et 4-Hydroxyphenyl 257-259 395 204 Me H Et 3-Methoxyphenyl 188-190 409 205 Cl CO₂H Et 4-Aminophenyl 226-228 458 206 Cl Cl t-Bu 3-Hydroxy-4-methoxy 505 phenyl 207 Cl Cl CHF₂ 3-Hydroxy-4-methoxy 499 phenyl 208 Cl Cl CH₂OH 3-Methoxyphenyl 227-229 209 Cl Cl i-Pr 3-(Ethoxycarbonyl- 174-175 methyl)phenyl 210 Cl Cl i-Pr 3-(carboxymethyl) 210-211 phenyl 211 Cl Cl i-Pr 3-(2-hydroxyethyl) 489 phenyl 212 Cl Cl n-Bu 3-Hydroxy-4-methoxy 505 phenyl 213 Me H i-Pr 4-(1-CH₃-piperidin-4- 576 ylN(CH₃)CH₂CONH)phenyl 214 Me H i-Pr 4-(1-CH₃-piperidin-4- 562 ylN(CH₃)CONH)phenyl 215 Me Cl i-Pr 4-(1-CH₃-piperidin-4- 596 ylN(CH₃)CONH)phenyl 216 Me Cl i-Pr 4-(1-CH₃-piperidin-4- 108-110 610 ylN(CH₃)CH₂CONH)phenyl 217 Me Cl i-Pr 4-aminophenyl 212-213 442 218 Me Cl i-Pr 4-(morpholin-4- 256-258 555 ylCONH)phenyl 219 Me Cl i-Pr 4-(4-CH₃-piperazin-1- 154-156 568 ylCONH)phenyl 220 Me Cl i-Pr 4-(4-CH₃-piperazin-1- 199-210 582 ylCH₂CONH)phenyl 221 Me Cl i-Pr 4-(Me₂NCH₂CONH)phenyl >300 561 HCl 222 Me Cl i-Pr 4-(morpholin-4-yl 246-249 569 CH₂CONH)phenyl 223 Cl Cl i-Pr 5-(Me₂NCH₂)-1-methyl 182-184 507 pyrrol-2-yl 224 Cl CH₂NH₂ i-Pr 3-Methoxyphenyl 472 225 Cl SO₂NH₂ i-Pr 3-Methoxyphenyl 244-245 520

TABLE X

Ex# R¹ mp. (° C.) MS 226 4-(N,N-Dimethyl glycinamido)phenyl 235-237 533 227 3-Hydroxyphenyl 227-229 449

TABLE XI

Ex. R⁶ mp (° C.) MS 228 CONHCH₂CH₂N(CH₃)₂ 203-205 543 229 CONHCH₂CH₂CH₃ 229-231 512 230 CCNHCH(CH₃)₂ 233-235 512 231 CONHCH₂Ph 239-240 560 232 CO-(4-CH₃-piperazin)-1-yl 128-130 555 233 CONHCH₂pyridin-3-yl amorphous 563 234 CONHCH₂pyridin-2-yl 188-190 563 235 CONHCH₂pyridin-4-yl 238-239 563 236 CONHCH₂CH₃ 226-228 498 237 CONHPh amorphous 546 238 CONHC(CH₃)₃ 222-224 528 239 CO-piperazin-1-yl amorphous 541 240 CONHcyclo-C₃H₅ 236-239 510 241 CONHpyridin-3-yl 256-258 549 242 CONHpyridin-4-yl amorphous 549 243 CONH(4-CH₃-piperazin)-1-yl amorphous 570 244 CONHpyridin-2-yl 237-239 549 245 CONHOCH₃ 204-206 502

TABLE XII

Ex.# R⁵ mp (° C.) MS 246 CONHCH₂CH₂N(CH₃)₂ 263-265 529 247 CONHCH₂Ph 247-249 546

By reacting a p-substituted aniline with suitable acylating agents and performing further synthetic manipulations as necessary, the following compounds were prepared:

TABLE XIII

Ex.# R² R⁷ (para) R⁷ (meta) mp (° C.) MS 248 c-Pr (CH₃)₂NCH₂CONH H 545 249 Et CH₃CONH H 488 250 Et CH₃OCONH H 504 251 Et CH₃NHCONH H 503 252 i-Pr CH₃OCONH H 518 253 i-Pr CH₃OCON(Me) H 532 254 Et (CH₃)₂NCH₂CONH H 531 255 i-Pr CH₃NHCONH HO 535 256 i-Pr CH₃NHCON(Me) H 235-237 531 257 i-Pr 4-CH₃-piperazin-1-ylN(Me) H 616 258 i-Pr (CH₃)₂NCH₂CON(Me) H 235-237 561 259 i-Pr CH₃NHCON(Me) H 235-237 531 260 i-Pr (CH₃)₂NCH₂CONH HO 255-258 563 261 i-Pr (+/−)-(CH₃)₂NCH(CH₃)CONH H 561 262 i-Pr (CH₃)₂NCH₂CONH MeO amorphous 577 263 i-Pr CH₃NHCONH MeO 258-261 264 i-Pr imidazol-1-ylCH₂CONH HO 586 265 i-Pr (CH₃)₂NCH₂CONH H 255-257 547 266 i-Pr 4-CH₃-piperazin-1-yl H 602 CH₂CONH 267 i-Pr CH₃NHCONH H 268-274 519 268 i-Pr morpholin-4-ylCH₂CONH H 252-255 589 269 i-Pr azetidin-1-ylCH₂CONH H 559 270 i-Pr (CH₃)₂NCH₂CH₂SO₂NH H 597.1011 271 i-Pr EtO₂CCH₂NHCONH H 229-230 589 272 i-Pr hydantoin-1-yl H >300 543 273 i-Pr HOCH₂CH₂NHCONH H 160-162 547.0799 274 i-Pr HO₂C(CH₂)₂CONH H 256-258 560 275 i-Pr imidazol-1-ylCH₂CONH H 276-278 570 276 i-Pr Morpholin-4-ylCH₂CH₂ H 634 NHCSNH 277 i-Pr HO₂CCH₂NHCONH H 561 278 i-Pr HO₂C(CH₂)₃CONH H 574 279 i-Pr H₂NCH₂CONH H >300 519 280 i-Pr CH₃NHCH₂CONH H amorphous 533.1029 281 i-Pr 4-F-phenyl CH₂NHCH₂CONH H 217-223 627 282 i-Pr pyrrolidin-1-ylCH₂CONH H 235-240 573 283 i-Pr pyrid-2-ylCH₂NHCH₂CONH H 610 284 i-Pr pyrid-3-ylCH₂NHCH₂CONH H 145-150 610 285 i-Pr pyrid-4-ylCH₂NHCH₂CONH H 180-185 610 286 i-Pr BocNHCH₂CH₂NHCH₂CONH H 662.1829 287 i-Pr HOCH₂CH(CH₃)NHCH₂CONH H 190-192 577 288 i-Pr CH₃CH(OH)CH₂NHCH₂CONH 152-160 577 289 i-Pr H₂NCH₂CH₂NHCH₂CONH H 562 290 i-Pr morpholin-4-ylCH₂CH₂ H 632 NHCH₂CONH 291 i-Pr 1-CH₃-piperidin-4-yl H 630 N(CH₃) CH₂CONH 292 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH H 188-190 604 293 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CONH H 590 294 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH OH 606 295 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH OMe 620 296 i-Pr (CH₃)₂NCH(CH₃)CONH H 561 297 i-Pr 1-CH₃-L-prolylNH H 298 i-Pr Homopiperazin-1-yl H 602.1610 CH₂CONH 299 i-Pr CH₃CH₂NHCH₂CONH H 547 300 i-Pr 4-(H₂NCH₂)piperidin-1-yl H amorphous 616 CH₂CONH 301 i-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH H 133-135 590.1610 302 i-Pr cyclo-C₃H₅NHCH₂CONH H 213-216 559 303 i-Pr Piperidin-4-ylCH₂NH H 616 CH₂CONH 304 i-Pr HO(CH₂)₃NHCH₂CONH H 200-205 575 305 i-Pr 1-Bocpiperidin-4-ylCH₂NH H 716 CH₂CONH 306 i-Pr HOCH₂CH₂NHCH₂CONH H 210-212 563 307 i-Pr cyclo-C₄H₇NHCH₂CONH H 225-228 573 308 i-Pr azetidin-3-ylCONH H 545 309 i-Pr D-prolylNH.HCl H 225-226 559 310 i-Pr Boc-D-prolylNH H 559.1185 311 i-Pr L-prolylNH.HCl H 225-226 659.1707 312 i-Pr Boc-L-prolylNH H 657 313 i-Pr piperidin-1-ylCH₂CH₂— H 213-215 630 NHCH₂CONH 314 i-Pr (CH₃)₂CHNHCH₂CONH H 130-135 559 315 i-Pr BocNHCH₂CH₂CONH H 631 316 i-Pr piperazin-2-yl-CONH H amorphous 547.1286 317 i-Pr 4-Me-piperazin-2-yl-CONH H amorphous 588.1448 318 i-Pr piperidin-1-ylNHCONH H 264-266 588 319 i-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H H 548 320 i-Pr pyrid-2-ylNHCONH H 277-281 321 i-Pr (CH₃)₂NCH₂CH₂NHCONH H 220-222 576 322 i-Pr (CH₃)₂NCH₂CH₂NHCONH OMe 244-248 606 323 i-Pr BocNHCH₂CH₂NHCONH H 208-210 646 324 i-Pr HO(CH₂)₄NHCONH H 208-210 577 325 i-Pr (CH₃)₂NNHCONH H 240-242 546 326 i-Pr (CH₃)₂N(CH₂)₃NHCONH H 590 327 i-Pr (CH₃)₂N(CH₂)₃NHCONH OMe 226-228 620 328 i-Pr 4-CH₃-homo-piperazin-1- H 602 yl-CONH 329 i-Pr CH₃SO₂NHCONH H 581 330 i-Pr CH₃ONHCONH H 534 331 i-Pr 1-CH₃-piperidin-4-yl H 616 N(CH₃)CONH 332 i-Pr 1-CH₃-piperidin-4-yl OH 632 N(CH₃)CONH 333 i-Pr 1-CH₃-piperidin-4-yl OMe 243-245 646 N(CH₃)CONH 334 i-Pr tetrahydrofur-2-yl H 587 CH₂NHCONH 335 i-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH H 589 336 i-Pr HOCH₂CH(CH₃)NHCONH H 156-158 561 337 i-Pr CH₃CH(OH)CH₂NHCONH H 561 338 i-Pr HOCH₂CH₂NHCONH H 222-225 547 339 i-Pr morpholin-4-ylNHCONH H 272-274 588 340 i-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH H 590 341 i-Pr 4-CH₃-piperazin-1-yl H 603 NHCONH 342 i-Pr 4-CH₃-piperazin-1-yl OH 619 NHCONH 343 i-Pr 4-CH₃-piperazin-1-yl OMe 245-246 633 NHCONH 344 i-Pr morpholin-4-yl H 618 CH₂CH₂NHCONH 345 i-Pr 4-CH₃-piperazin-1-ylCONH H 588 346 i-Pr piperazin-1-ylCONH.HCl H 574 347 Et 4-CH₃-piperazin-1-ylCONH H 574 348 Et (CH₃)₂NCH₂CH₂NHCONH H 563 349 Et pyrid-2-ylNHCONH H amorphous 582 350 Et pyrid-4-ylNHCONH H amorphous 582 351 i-Pr H MeN 533 HCO NHC H₂ 352 i-Pr (+/−)-2-(Me₂NCH₂)piperid- H 630 1-ylCONH 353 i-Pr (+/−)-2-(Me₂NCH₂)piperid- OH 646 1-ylCONH.CF₃CO₂H 354 i-Pr (+/−)-2-(Me₂NCH₂)piperid- OMe 131-135 660 1-ylCONH 355 i-Pr CH₃NCH₂CH₂N(CH₃)CONH OMe 146-148 606 356 i-Pr (CH₃)₂NCH₂CH₂NCO H 278-280 561 357 i-Pr (CH₃)NCH₂CH₂N(CH₃)CO H 561 358 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CO H 575

Following procedures similar to those used to synthesize the examples above, the following compounds were prepared or could be prepared:

TABLE XIV

Ex. # R² R⁷(para) R⁷(meta) MS 1 i-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH H 616 2 i-Pr pyrrolidin-1-ylCH₂CH₂NHCONH OMe 632 3 i-Pr pyrrolidin-1-ylCH₂CH₂NHCONH OH 618 4 i-Pr pyrrolidin-1-ylCH₂CH₂NHCONH H 602 5 i-Pr 2-CH₃-piperazin-1-ylCONH H 6 i-Pr 3-CH₃-piperazin-1-ylCH₂CONH H 602 7 i-Pr trans-2,5-di-CH₃-piperazin-1- H 616 ylCH₂CONH 8 i-Pr cis-2,6-di-CH₃-piperazin-1- H ylCH₂CONH 9 i-Pr cis-3,4-di-CH₃-piperazin-1- H 616 ylCH₂CONH 10 i-Pr cis-3,5-di-CH₃-piperazin-1- H ylCH₂CONH 11 i-Pr trans-2,6-di-CH₃-piperazin-1- H ylCH₂CONH 12 i-Pr trans-3,5-di-CH₃-piperazin-1- H ylCH₂CONH 13 i-Pr (R)-1-Ethylpyrrolidin-2- H ylCH₂NHCONH 14 i-Pr (S)-1-Ethylpyrrolidin-2- H ylCH₂NHCONH 15 i-Pr 5-CH₃-pyrazin-2- H ylCH₂NHCH₂CONH 16 i-Pr (CH₃)₂NCH₂CH₂CH₂OCONH H 591 17 i-Pr (+/−)—N—(CH₃)piperidin-3- H 617 ylCH₂OCONH 18 i-Pr (+/−)—N—(CH₃)piperidin-3-ylOCONH H 603 19 i-Pr (+/−)—N—(CH₃)piperidin-2- H 617 ylCH₂OCONH 20 i-Pr (+/−)—N—(CH₃)pyrrolidin-3- H 589 ylOCONH 21 i-Pr 2-CH₃-piperazin-1-ylCH₂CONH H 22 i-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH H 23 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CONH H 590 24 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CO H 575 25 i-Pr 2-CH₃-piperazin-1-ylCONH H 26 i-Pr 3-CH₃-piperazin-1-ylCH₂CONH H 27 i-Pr trans-2,5-di-CH₃-piperazin-1- H ylCH₂CONH 28 i-Pr cis-2,6-di-CH₃-piperazin-1- H ylCH₂CONH 29 i-Pr cis-3,5-di-CH₃-piperazin-1- H ylCH₂CONH 30 i-Pr trans-2,6-di-CH₃-piperazin-1- H ylCH₂CONH

TABLE XV (a)

(b)

Ex. # R² R⁷ 1 i-Pr 1-CH₃-piperazin-4-ylCH₂CONH 2 i-Pr BocNHSO₂NH 3 i-Pr morpholin-4-ylCH₂CONH 4 i-Pr azetidin-1-ylCH₂CONH 5 i-Pr (CH₃)₂NCH₂CH₂SO₂NH 6 i-Pr EtO₂CCH₂NHCONH 7 i-Pr HOCH₂CH₂NHCONH 8 i-Pr Hydantoin-1-yl 9 i-Pr HOCH₂CH₂NHCONH 10 i-Pr HO₂C(CH₂)₂CONH 11 i-Pr imidazol-1-ylCH₂CONH 12 i-Pr Morpholin-4-ylCH₂CH₂NHCSNH 13 i-Pr HO₂CCH₂NHCONH 14 i-Pr HO₂C(CH₂)₃CONH 15 i-Pr (CH₃)₂NCH₂CONH 16 i-Pr H₂NCH₂CONH 17 i-Pr CH₃NHCH₂CONH 18 i-Pr 4-F-phenylCH₂NHCH₂CONH 19 i-Pr pyrrolidin-1-ylCH₂CONH 20 i-Pr pyrid-2-ylCH₂NHCH₂CONH 21 i-Pr pyrid-3-ylCH₂NHCH₂CONH 22 i-Pr pyrid-4-ylCH₂NHCH₂CONH 23 i-Pr BocNHCH₂CH₂NHCH₂CONH 24 i-Pr HOCH₂CH(CH₃)NHCH₂CONH 25 i-Pr CH₃CH(OH)CH₂NHCH₂CONH 26 i-Pr H₂NCH₂CH₂NHCH₂CONH 27 i-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH 28 i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 29 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 30 i-Pr piperazin-1-ylCH₂CONH 31 i-Pr (CH₃)₂NCH(CH₃)CONH 32 i-Pr 1-CH₃-L-prolylNH 33 i-Pr homopiperazin-1-ylCH₂CONH 34 i-Pr CH₃CH₂NHCH₂CONH 35 i-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 36 i-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH 37 i-Pr H₂NCH₂CONH 38 i-Pr cyclo-C₃H₅NHCH₂CONH 39 i-Pr piperidin-4-ylCH₂NHCH₂CONH 40 i-Pr HO(CH₂)₃NHCH₂CONH 41 i-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 42 i-Pr HOCH₂CH₂NHCH₂CONH 43 i-Pr cyclo-C₄H₇NHCH₂CONH 44 i-Pr azetidin-3-ylCONH 45 i-Pr D-prolylNH.HCl 46 i-Pr Boc-D-prolylNH 47 i-Pr L-prolylNH.HCl 48 i-Pr Boc-L-prolylNH 49 i-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH 50 i-Pr (CH₃)₂CHNHCH₂CONH 51 i-Pr BocNHCH₂CH₂CONH 52 i-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 53 i-Pr 2-CH₃-piperazin-1-ylCONH 54 i-Pr 3-CH₃-piperazin-1-ylCH₂CONH 55 i-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 56 i-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 57 i-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 58 i-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 59 i-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 60 i-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 61 i-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 62 i-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH 63 i-Pr piperazin-2-yl-CONH 64 i-Pr 4-Me-piperazin-2-ylCONH

TABLE XVI (a)

(b)

(c)

Ex. # R² R⁷ 1 cyc-Bu (CH₃)₂NCH₂CONH 2 cyc-Bu 1-CH₃-piperazin-4-ylCH₂CONH 3 cyc-Bu CH₃NHCONH 4 cyc-Bu morpholin-4-ylCH₂CONH 5 cyc-Bu azetidin-1-ylCH₂CONH 6 cyc-Bu (CH₃)₂NCH₂CH₂SO₂NH 7 cyc-Bu EtO₂CCH₂NHCONH 8 cyc-Bu Hydantoin-1-yl 9 cyc-Bu HOCH₂CH₂NHCONH 10 cyc-Bu HO₂C(CH₂)₂CONH 11 cyc-Bu imidazol-1-ylCH₂CONH 12 cyc-Bu Morpholin-4-ylCH₂CH₂NHCSNH 13 cyc-Bu HO₂CCH₂NHCONH 14 cyc-Bu HO₂C(CH₂)₃CONH 15 cyc-Bu H₂NCH₂CONH 16 cyc-Bu CH₃NHCH₂CONH 17 cyc-Bu 4-F-phenylCH₂NHCH₂CONH 18 cyc-Bu pyrrolidin-1-ylCH₂CONH 19 cyc-Bu pyrid-2-ylCH₂NHCH₂CONH 20 cyc-Bu pyrid-3-ylCH₂NHCH₂CONH 21 cyc-Bu pyrid-4-ylCH₂NHCH₂CONH 22 cyc-Bu BocNHCH₂CH₂NHCH₂CONH 23 cyc-Bu HOCH₂CH(CH₃)NHCH₂CONH 24 cyc-Bu CH₃CH(OH)CH₂NHCH₂CONH 25 cyc-Bu H₂NCH₂CH₂NHCH₂CONH 26 cyc-Bu morpholin-4-ylCH₂CH₂NHCH₂CONH 27 cyc-Bu 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 28 cyc-Bu (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 29 cyc-Bu (CH₃)₂NCH(CH₃)CONH 30 cyc-Bu 1-CH₃-L-prolylNH 31 cyc-Bu Homopiperazin-1-ylCH₂CONH 32 cyc-Bu CH₃CH₂NHCH₂CONH 33 cyc-Bu 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 34 cyc-Bu (CH₃)₂NCH₂CH₂NHCH₂CONH 35 cyc-Bu cyclo-C₃H₅NHCH₂CONH 36 cyc-Bu Piperidin-4-ylCH₂NHCH₂CONH 37 cyc-Bu HO(CH₂)₃NHCH₂CONH 38 cyc-Bu 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 39 cyc-Bu HOCH₂CH₂NHCH₂CONH 40 cyc-Bu cyclo-C₄H₇NHCH₂CONH 41 cyc-Bu azetidin-3-ylCONH 42 cyc-Bu D-prolylNH.HCl 43 cyc-Bu Boc-D-prolylNH 44 cyc-Bu L-prolylNH.HCl 45 cyc-Bu Boc-L-prolylNH 46 cyc-Bu piperidin-1-ylCH₂CH₂NHCH₂CONH 47 cyc-Bu (CH₃)₂CHNHCH₂CONH 48 cyc-Bu BocNHCH₂CH₂CONH 49 cyc-Bu piperazin-2-yl-CONH 50 cyc-Bu 4-Me-piperazin-2-yl-CONH 51 cyc-Bu piperidin-1-ylNHCONH 52 cyc-Bu H₂NCH₂CH₂NHCONH.F₃CCO₂H 53 cyc-Bu pyrid-2-ylNHCONH 54 cyc-Bu (CH₃)₂NCH₂CH₂NHCONH 55 cyc-Bu BocNHCH₂CH₂NHCONH 56 cyc-Bu HO(CH₂)₄NHCONH 57 cyc-Bu (CH₃)₂NNHCONH 58 cyc-Bu (CH₃)₂N(CH₂)₃NHCONH 59 cyc-Bu 1-CH₃-homopiperazin-4-yl-CONH 60 cyc-Bu CH₃SO₂NHCONH 61 cyc-Bu CH₃ONHCONH 62 cyc-Bu (CH₃)₂NCH₂CH₂NHCONH 63 cyc-Bu 1-CH₃-piperidin-4-ylN(CH₃)CONH 64 cyc-Bu tetrahydrofur-2-ylCH₂NHCONH 65 cyc-Bu CH₃(CH₂)₂CH(OH)CH₂NHCONH 66 cyc-Bu HOCH₂CH(CH₃)NHCONH 67 cyc-Bu CH₃CH(OH)CH₂NHCONH 68 cyc-Bu HOCH₂CH₂NHCONH 69 cyc-Bu morpholin-4-ylNHCONH 70 cyc-Bu (CH₃)₂NCH(CH₃)CH₂NHCONH 71 cyc-Bu 1-CH₃-piperazin-4-ylNHCONH 72 cyc-Bu morpholin-4-ylCH₂CH₂NHCONH 73 cyc-Bu 1-CH₃-piperazin-4-ylCONH 74 cyc-Bu pyrid-2-ylNHCONH 75 cyc-Bu pyrid-4-ylNHCONH 76 cyc-Bu pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 77 cyc-Bu 2-CH₃-piperazin-1-ylCONH 78 cyc-Bu 3-CH₃-piperazin-1-ylCH₂CONH 79 cyc-Bu trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 80 cyc-Bu cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 81 cyc-Bu cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 82 cyc-Bu trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 83 cyc-Bu trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 84 cyc-Bu (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 cyc-Bu (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 86 cyc-Bu 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

TABLE XVII

Ex.# R² R⁷(para) R⁷(meta) 1 i-Pr (CH₃)₂NCH₂CONH Me 2 i-Pr 1-CH₃-piperazin-4-ylCH₂CONH Me 3 i-Pr CH₃NHCONH Me 4 i-Pr morpholin-4-ylCH₂CONH Me 5 i-Pr azetidin-1-ylCH₂CONH Me 6 i-Pr (CH₃)₂NCH₂CH₂SO₂NH Me 7 i-Pr EtO₂CCH₂NHCONH Me 8 i-Pr Hydantoin-1-yl Me 9 i-Pr HOCH₂CH₂NHCONH Me 10 i-Pr HO₂C(CH₂)₂CONH Me 11 i-Pr imidazol-1-ylCH₂CONH Me 12 i-Pr Morpholin-4-ylCH₂CH₂NHCSNH Me 13 i-Pr HO₂CCH₂NHCONH Me 14 i-Pr HO₂C(CH₂)₃CONH Me 15 i-Pr H₂NCH₂CONH Me 16 i-Pr CH₃NHCH₂CONH Me 17 i-Pr 4-F-phenylCH₂NHCH₂CONH Me 18 i-Pr pyrrolidin-1-ylCH₂CONH Me 19 i-Pr pyrid-2-ylCH₂NHCH₂CONH Me 20 i-Pr pyrid-3-ylCH₂NHCH₂CONH Me 21 i-Pr pyrid-4-ylCH₂NHCH₂CONH Me 22 i-Pr BocNHCH₂CH₂NHCH₂CONH Me 23 i-Pr HOCH₂CH(CH₃)NHCH₂CONH Me 24 i-Pr CH₃CH(OH)CH₂NHCH₂CONH Me 25 i-Pr H₂NCH₂CH₂NHCH₂CONH Me 26 i-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH Me 27 i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH Me 28 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH Me 29 i-Pr (CH₃)₂NCH(CH₃)CONH Me 30 i-Pr 1-CH₃-L-prolylNH Me 31 i-Pr Homopiperazin-1-ylCH₂CONH Me 32 i-Pr CH₃CH₂NHCH₂CONH Me 33 i-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH Me 34 i-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH Me 35 i-Pr cyclo-C₃H₅NHCH₂CONH Me 36 i-Pr Piperidin-4-ylCH₂NHCH₂CONH Me 37 i-Pr HO(CH₂)₃NHCH₂CONH Me 38 i-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH Me 39 i-Pr HOCH₂CH₂NHCH₂CONH Me 40 i-Pr cyclo-C₄H₇NHCH₂CONH Me 41 i-Pr azetidin-3-ylCONH Me 42 i-Pr D-prolylNH.HCl Me 43 i-Pr Boc-D-prolylNH Me 44 i-Pr L-prolylNH.HCl Me 45 i-Pr Boc-L-prolylNH Me 46 i-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH Me 47 i-Pr (CH₃)₂CHNHCH₂CONH Me 48 i-Pr BocNHCH₂CH₂CONH Me 49 i-Pr piperazin-2-yl-CONH Me 50 i-Pr 4-Me-piperazin-2-yl-CONH Me 51 i-Pr piperidin-1-ylNHCONH Me 52 i-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H Me 53 i-Pr pyrid-2-ylNHCONH Me 54 i-Pr (CH₃)₂NCH₂CH₂NHCONH Me 55 i-Pr BocNHCH₂CH₂NHCONH Me 56 i-Pr HO(CH₂)₄NHCONH Me 57 i-Pr (CH₃)₂NNHCONH Me 58 i-Pr (CH₃)₂N(CH₂)₃NHCONH Me 59 i-Pr 1-CH₃-homopiperazin-4-yl-CONH Me 60 i-Pr CH₃SO₂NHCONH Me 61 i-Pr CH₃ONHCONH Me 62 i-Pr (CH₃)₂NCH₂CH₂NHCONH Me 63 i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CONH Me 64 i-Pr tetrahydrofur-2-ylCH₂NHCONH Me 65 i-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH Me 66 i-Pr HOCH₂CH(CH₃)NHCONH Me 67 i-Pr CH₃CH(OH)CH₂NHCONH Me 68 i-Pr HOCH₂CH₂NHCONH Me 69 i-Pr morpholin-4-ylNHCONH Me 70 i-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH Me 71 i-Pr 1-CH₃-piperazin-4-ylNHCONH Me 72 i-Pr morpholin-4-ylCH₂CH₂NHCONH Me 73 i-Pr 1-CH₃-piperazin-4-ylCONH Me 74 i-Pr pyrid-2-ylNHCONH Me 75 i-Pr pyrid-4-ylNHCONH Me 76 i-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH Me 77 i-Pr 2-CH₃-piperazin-1-ylCONH Me 78 i-Pr 3-CH₃-piperazin-1-ylCH₂CONH Me 79 i-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH Me 80 i-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH Me 81 i-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH Me 82 i-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH Me 83 i-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH Me 84 i-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH Me 85 i-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH Me 86 i-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH Me

TABLE XVIII

Ex.# R² R⁷(meta) R⁷(ortho) 1 i-Pr 1-CH₃-piperazin-4-ylCH₂CONH Me 2 i-Pr CH₃NHCONH Me 3 i-Pr morpholin-4-ylCH₂CONH Me 4 i-Pr azetidin-1-ylCH₂CONH Me 5 i-Pr (CH₃)₂NCH₂CH₂SO₂NH Me 6 i-Pr EtO₂CCH₂NHCONH Me 7 i-Pr Hydantoin-1-yl Me 8 i-Pr HOCH₂CH₂NHCONH Me 9 i-Pr HO₂C(CH₂)₂CONH Me 10 i-Pr imidazol-1-ylCH₂CONH Me 11 i-Pr Morpholin-4-ylCH₂CH₂NHCSNH Me 12 i-Pr HO₂CCH₂NHCONH Me 13 i-Pr HO₂C(CH₂)₃CONH Me 14 i-Pr H₂NCH₂CONH Me 15 i-Pr CH₃NHCH₂CONH Me 16 i-Pr 4-F-phenylCH₂NHCH₂CONH Me 17 i-Pr pyrrolidin-1-ylCH₂CONH Me 18 i-Pr pyrid-2-ylCH₂NHCH₂CONH Me 19 i-Pr pyrid-3-ylCH₂NHCH₂CONH Me 20 i-Pr pyrid-4-ylCH₂NHCH₂CONH Me 21 i-Pr BocNHCH₂CH₂NHCH₂CONH Me 22 i-Pr HOCH₂CH(CH₃)NHCH₂CONH Me 23 i-Pr CH₃CH(OH)CH₂NHCH₂CONH Me 24 i-Pr H₂NCH₂CH₂NHCH₂CONH Me 25 i-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH Me 26 i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH Me 27 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH Me 28 i-Pr (CH₃)₂NCH(CH₃)CONH Me 29 i-Pr 1-CH₃-L-prolylNH Me 30 i-Pr Homopiperazin-1-ylCH₂CONH Me 31 i-Pr CH₃CH₂NHCH₂CONH Me 32 i-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH Me 33 i-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH Me 34 i-Pr cyclo-C₃H₅NHCH₂CONH Me 35 i-Pr Piperidin-4-ylCH₂NHCH₂CONH Me 36 i-Pr HO(CH₂)₃NHCH₂CONH Me 37 i-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH Me 38 i-Pr HOCH₂CH₂NHCH₂CONH Me 39 i-Pr cyclo-C₄H₇NHCH₂CONH Me 40 i-Pr azetidin-3-ylCONH Me 41 i-Pr D-prolylNH.HCl Me 42 i-Pr Boc-D-prolylNH Me 43 i-Pr L-prolylNH.HCl Me 44 i-Pr Boc-L-prolylNH Me 45 i-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH Me 46 i-Pr (CH₃)₂CHNHCH₂CONH Me 47 i-Pr BocNHCH₂CH₂CONH Me 48 i-Pr piperazin-2-yl-CONH Me 49 i-Pr 4-Me-piperazin-2-yl-CONH Me 50 i-Pr piperidin-1-ylNHCONH Me 51 i-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H Me 52 i-Pr pyrid-2-ylNHCONH Me 53 i-Pr (CH₃)₂NCH₂CH₂NHCONH Me 54 i-Pr BocNHCH₂CH₂NHCONH Me 55 i-Pr HO(CH₂)₄NHCONH Me 56 i-Pr (CH₃)₂NNHCONH Me 57 i-Pr (CH₃)₂N(CH₂)₃NHCONH Me 58 i-Pr 1-CH₃-homopiperazin-4-yl-CONH Me 59 i-Pr CH₃SO₂NHCONH Me 60 i-Pr CH₃ONHCONH Me 61 i-Pr (CH₃)₂NCH₂CH₂NHCONH Me 62 i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CONH Me 63 i-Pr tetrahydrofur-2-ylCH₂NHCONH Me 64 i-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH Me 65 i-Pr HOCH₂CH(CH₃)NHCONH Me 66 i-Pr CH₃CH(OH)CH₂NHCONH Me 67 i-Pr HOCH₂CH₂NHCONH Me 68 i-Pr morpholin-4-ylNHCONH Me 69 i-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH Me 70 i-Pr 1-CH₃-piperazin-4-ylNHCONH Me 71 i-Pr morpholin-4-ylCH₂CH₂NHCONH Me 72 i-Pr 1-CH₃-piperazin-4-ylCONH Me 73 i-Pr pyrid-2-ylNHCONH Me 74 i-Pr pyrid-4-ylNHCONH Me 75 i-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH Me 76 i-Pr 2-CH₃-piperazin-1-ylCONH Me 77 i-Pr 3-CH₃-piperazin-1-ylCH₂CONH Me 78 i-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH Me 79 i-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH Me 80 i-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH Me 81 i-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH Me 82 i-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH Me 83 i-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH Me 84 i-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH Me 85 i-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH Me

TABLE XIX

Ex.# R² R⁷(para) R⁷(ortho) 1 i-Pr (CH₃)₂NCH₂CONH Me 2 i-Pr 1-CH₃-piperazin-4-ylCH₂CONH Me 3 i-Pr CH₃NHCONH Me 4 i-Pr morpholin-4-ylCH₂CONH Me 5 i-Pr azetidin-1-ylCH₂CONH Me 6 i-Pr (CH₃)₂NCH₂CH₂SO₂NH Me 7 i-Pr EtO₂CCH₂NHCONH Me 8 i-Pr Hydantoin-1-yl Me 9 i-Pr HOCH₂CH₂NHCONH Me 10 i-Pr HO₂C(CH₂)₂CONH Me 11 i-Pr imidazol-1-ylCH₂CONH Me 12 i-Pr Morpholin-4-ylCH₂CH₂NHCSNH Me 13 i-Pr HO₂CCH₂NHCONH Me 14 i-Pr HO₂C(CH₂)₃CONH Me 15 i-Pr H₂NCH₂CONH Me 16 i-Pr CH₃NHCH₂CONH Me 17 i-Pr 4-F-phenylCH₂NHCH₂CONH Me 18 i-Pr pyrrolidin-1-ylCH₂CONH Me 19 i-Pr pyrid-2-ylCH₂NHCH₂CONH Me 20 i-Pr pyrid-3-ylCH₂NHCH₂CONH Me 21 i-Pr pyrid-4-ylCH₂NHCH₂CONH Me 22 i-Pr BocNHCH₂CH₂NHCH₂CONH Me 23 i-Pr HOCH₂CH(CH₃)NHCH₂CONH Me 24 i-Pr CH₃CH(OH)CH₂NHCH₂CONH Me 25 i-Pr H₂NCH₂CH₂NHCH₂CONH Me 26 i-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH Me 27 i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH Me 28 i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH Me 29 i-Pr (CH₃)₂NCH(CH₃)CONH Me 30 i-Pr 1-CH₃-L-prolylNH Me 31 i-Pr Homopiperazin-1-ylCH₂CONH Me 32 i-Pr CH₃CH₂NHCH₂CONH Me 33 i-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH Me 34 i-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH Me 35 i-Pr cyclo-C₃H₅NHCH₂CONH Me 36 i-Pr Piperidin-4-ylCH₂NHCH₂CONH Me 37 i-Pr HO(CH₂)₃NHCH₂CONH Me 38 i-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH Me 39 i-Pr HOCH₂CH₂NHCH₂CONH Me 40 i-Pr cyclo-C₄H₇NHCH₂CONH Me 41 i-Pr azetidin-3-ylCONH Me 42 i-Pr D-prolylNH.HCl Me 43 i-Pr Boc-D-prolylNH Me 44 i-Pr L-prolylNH.HCl Me 45 i-Pr Boc-L-prolylNH Me 46 i-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH Me 47 i-Pr (CH₃)₂CHNHCH₂CONH Me 48 i-Pr BocNHCH₂CH₂CONH Me 49 i-Pr piperazin-2-yl-CONH Me 50 i-Pr 4-Me-piperazin-2-yl-CONH Me 51 i-Pr piperidin-1-ylNHCONH Me 52 i-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H Me 53 i-Pr pyrid-2-ylNHCONH Me 54 i-Pr (CH₃)₂NCH₂CH₂NHCONH Me 55 i-Pr BocNHCH₂CH₂NHCONH Me 56 i-Pr HO(CH₂)₄NHCONH Me 57 i-Pr (CH₃)₂NNHCONH Me 58 i-Pr (CH₃)₂N(CH₂)₃NHCONH Me 59 i-Pr 1-CH₃-homopiperazin-4-yl-CONH Me 60 i-Pr CH₃SO₂NHCONH Me 61 i-Pr CH₃ONHCONH Me 62 i-Pr (CH₃)₂NCH₂CH₂NHCONH Me 63 i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CONH Me 64 i-Pr tetrahydrofur-2-ylCH₂NHCONH Me 65 i-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH Me 66 i-Pr HOCH₂CH(CH₃)NHCONH Me 67 i-Pr CH₃CH(OH)CH₂NHCONH Me 68 i-Pr HOCH₂CH₂NHCONH Me 69 i-Pr morpholin-4-ylNHCONH Me 70 i-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH Me 71 i-Pr 1-CH₃-piperazin-4-ylNHCONH Me 72 i-Pr morpholin-4-ylCH₂CH₂NHCONH Me 73 i-Pr 1-CH₃-piperazin-4-ylCONH Me 74 i-Pr pyrid-2-ylNHCONH Me 75 i-Pr pyrid-4-ylNHCONH Me 76 i-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH Me 77 i-Pr 2-CH₃-piperazin-1-ylCONH Me 78 i-Pr 3-CH₃-piperazin-1-ylCH₂CONH Me 79 i-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH Me 80 i-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH Me 81 i-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH Me 82 i-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH Me 83 i-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH Me 84 i-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH Me 85 i-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH Me 86 i-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH Me

TABLE XX (a)

(b)

(c)

Ex. # R² R⁷ 1 Et 1-CH₃-piperazin-4-ylCH₂CONH 2 Et CH₃NHCONH 3 Et morpholin-4-ylCH₂CONH 4 Et azetidin-1-ylCH₂CONH 5 Et (CH₃)₂NCH₂CH₂SO₂NH 6 Et EtO₂CCH₂NHCONH 7 Et Hydantoin-1-yl 8 Et HOCH₂CH₂NHCONH 9 Et HO₂C(CH₂)₂CONH 10 Et imidazol-1-ylCH₂CONH 11 Et Morpholin-4-ylCH₂CH₂NHCSNH 12 Et HO₂CCH₂NHCONH 13 Et HO₂C(CH₂)₃CONH 14 Et H₂NCH₂CONH 15 Et CH₃NHCH₂CONH 16 Et 4-F-phenylCH₂NHCH₂CONH 17 Et pyrrolidin-1-ylCH₂CONH 18 Et pyrid-2-ylCH₂NHCH₂CONH 19 Et pyrid-3-ylCH₂NHCH₂CONH 20 Et pyrid-4-ylCH₂NHCH₂CONH 21 Et BocNHCH₂CH₂NHCH₂CONH 22 Et HOCH₂CH(CH₃)NHCH₂CONH 23 Et CH₃CH(OH)CH₂NHCH₂CONH 24 Et H₂NCH₂CH₂NHCH₂CONH 25 Et morpholin-4-ylCH₂CH₂NHCH₂CONH 26 Et 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 27 Et (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 28 Et (CH₃)₂NCH(CH₃)CONH 29 Et 1-CH₃-L-prolylNH 30 Et Homopiperazin-1-ylCH₂CONH 31 Et CH₃CH₂NHCH₂CONH 32 Et 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 33 Et (CH₃)₂NCH₂CH₂NHCH₂CONH 34 Et cyclo-C₃H₅NHCH₂CONH 35 Et Piperidin-4-ylCH₂NHCH₂CONH 36 Et HO(CH₂)₃NHCH₂CONH 37 Et 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 38 Et HOCH₂CH₂NHCH₂CONH 39 Et cyclo-C₄H₇NHCH₂CONH 40 Et azetidin-3-ylCONH 41 Et D-prolylNH.HCl 42 Et Boc-D-prolylNH 43 Et L-prolylNH.HCl 44 Et Boc-L-prolylNH 45 Et piperidin-1-ylCH₂CH₂NHCH₂CONH 46 Et (CH₃)₂CHNHCH₂CONH 47 Et BocNHCH₂CH₂CONH 48 Et piperazin-2-yl-CONH 49 Et 4-Me-piperazin-2-yl-CONH 50 Et piperidin-1-ylNHCONH 51 Et H₂NCH₂CH₂NHCONH.F₃CCO₂H 52 Et pyrid-2-ylNHCONH 53 Et (CH₃)₂NCH₂CH₂NHCONH 54 Et BocNHCH₂CH₂NHCONH 55 Et HO(CH₂)₄NHCONH 56 Et (CH₃)₂NNHCONH 57 Et (CH₃)₂N(CH₂)₃NHCONH 58 Et 1-CH₃-homopiperazin-4-yl-CONH 59 Et CH₃SO₂NHCONH 60 Et CH₃ONHCONH 61 Et (CH₃)₂NCH₂CH₂NHCONH 62 Et 1-CH₃-piperidin-4-ylN(CH₃)CONH 63 Et tetrahydrofur-2-ylCH₂NHCONH 64 Et CH₃(CH₂)₂CH(OH)CH₂NHCONH 65 Et HOCH₂CH(CH₃)NHCONH 66 Et CH₃CH(OH)CH₂NHCONH 67 Et HOCH₂CH₂NHCONH 68 Et morpholin-4-ylNHCONH 69 Et (CH₃)₂NCH(CH₃)CH₂NHCONH 70 Et 1-CH₃-piperazin-4-ylNHCONH 71 Et morpholin-4-ylCH₂CH₂NHCONH 72 Et 1-CH₃-piperazin-4-ylCONH 73 Et pyrid-2-ylNHCONH 74 Et pyrid-4-ylNHCONH 75 Et pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 76 Et 2-CH₃-piperazin-1-ylCONH 77 Et 3-CH₃-piperazin-1-ylCH₂CONH 78 Et trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 79 Et cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 80 Et cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 81 Et trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 82 Et trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 83 Et (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 84 Et (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 Et 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

TABLE XXI (a)

(b)

(c)

Ex. # R² R⁷ 1 cyc-Pr 1-CH₃-piperazin-4-ylCH₂CONH 2 cyc-Pr CH₃NHCONH 3 cyc-Pr morpholin-4-ylCH₂CONH 4 cyc-Pr azetidin-1-ylCH₂CONH 5 cyc-Pr (CH₃)₂NCH₂CH₂SO₂NH 6 cyc-Pr EtO₂CCH₂NHCONH 7 cyc-Pr Hydantoin-1-yl 8 cyc-Pr HOCH₂CH₂NHCONH 9 cyc-Pr HO₂C(CH₂)₂CONH 10 cyc-Pr imidazol-1-ylCH₂CONH 11 cyc-Pr Morpholin-4-ylCH₂CH₂NHCSNH 12 cyc-Pr HO₂CCH₂NHCONH 13 cyc-Pr HO₂C(CH₂)₃CONH 14 cyc-Pr H₂NCH₂CONH 15 cyc-Pr CH₃NHCH₂CONH 16 cyc-Pr 4-F-phenylCH₂NHCH₂CONH 17 cyc-Pr pyrrolidin-1-ylCH₂CONH 18 cyc-Pr pyrid-2-ylCH₂NHCH₂CONH 19 cyc-Pr pyrid-3-ylCH₂NHCH₂CONH 20 cyc-Pr pyrid-4-ylCH₂NHCH₂CONH 21 cyc-Pr BocNHCH₂CH₂NHCH₂CONH 22 cyc-Pr HOCH₂CH(CH₃)NHCH₂CONH 23 cyc-Pr CH₃CH(OH)CH₂NHCH₂CONH 24 cyc-Pr H₂NCH₂CH₂NHCH₂CONH 25 cyc-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH 26 cyc-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 27 cyc-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 28 cyc-Pr (CH₃)₂NCH(CH₃)CONH 29 cyc-Pr 1-CH₃-L-prolylNH 30 cyc-Pr Homopiperazin-1-ylCH₂CONH 31 cyc-Pr CH₃CH₂NHCH₂CONH 32 cyc-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 33 cyc-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH 34 cyc-Pr cyclo-C₃H₅NHCH₂CONH 35 cyc-Pr Piperidin-4-ylCH₂NHCH₂CONH 36 cyc-Pr HO(CH₂)₃NHCH₂CONH 37 cyc-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 38 cyc-Pr HOCH₂CH₂NHCH₂CONH 39 cyc-Pr cyclo-C₄H₇NHCH₂CONH 40 cyc-Pr azetidin-3-ylCONH 41 cyc-Pr D-prolylNH.HCl 42 cyc-Pr Boc-D-prolylNH 43 cyc-Pr L-prolylNH.HCl 44 cyc-Pr Boc-L-prolylNH 45 cyc-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH 46 cyc-Pr (CH₃)₂CHNHCH₂CONH 47 cyc-Pr BocNHCH₂CH₂CONH 48 cyc-Pr piperazin-2-yl-CONH 49 cyc-Pr 4-Me-piperazin-2-yl-CONH 50 cyc-Pr piperidin-1-ylNHCONH 51 cyc-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H 52 cyc-Pr pyrid-2-ylNHCONH 53 cyc-Pr (CH₃)₂NCH₂CH₂NHCONH 54 cyc-Pr BocNHCH₂CH₂NHCONH 55 cyc-Pr HO(CH₂)₄NHCONH 56 cyc-Pr (CH₃)₂NNHCONH 57 cyc-Pr (CH₃)₂N(CH₂)₃NHCONH 58 cyc-Pr 1-CH₃-homopiperazin-4-yl-CONH 59 cyc-Pr CH₃SO₂NHCONH 60 cyc-Pr CH₃ONHCONH 61 cyc-Pr (CH₃)₂NCH₂CH₂NHCONH 62 cyc-Pr 1-CH₃-piperidin-4-ylN(CH₃)CONH 63 cyc-Pr tetrahydrofur-2-ylCH₂NHCONH 64 cyc-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH 65 cyc-Pr HOCH₂CH(CH₃)NHCONH 66 cyc-Pr CH₃CH(OH)CH₂NHCONH 67 cyc-Pr HOCH₂CH₂NHCONH 68 cyc-Pr morpholin-4-ylNHCONH 69 cyc-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH 70 cyc-Pr 1-CH₃-piperazin-4-ylNHCONH 71 cyc-Pr morpholin-4-ylCH₂CH₂NHCONH 72 cyc-Pr 1-CH₃-piperazin-4-ylCONH 73 cyc-Pr pyrid-2-ylNHCONH 74 cyc-Pr pyrid-4-ylNHCONH 75 cyc-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 76 cyc-Pr 2-CH₃-piperazin-1-ylCONH 77 cyc-Pr 3-CH₃-piperazin-1-ylCH₂CONH 78 cyc-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 79 cyc-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 80 cyc-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 81 cyc-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 82 cyc-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 83 cyc-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 84 cyc-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 cyc-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

TABLE XXII (a)

(b)

(c)

Ex. # R² R⁷ 1 1-Methylcyc-Pr 1-CH₃-piperazin-4-ylCH₂CONH 2 1-Methylcyc-Pr CH₃NHCONH 3 1-Methylcyc-Pr morpholin-4-ylCH₂CONH 4 1-Methylcyc-Pr azetidin-1-ylCH₂CONH 5 1-Methylcyc-Pr (CH₃)₂NCH₂CH₂SO₂NH 6 1-Methylcyc-Pr EtO₂CCH₂NHCONH 7 1-Methylcyc-Pr Hydantoin-1-yl 8 1-Methylcyc-Pr HOCH₂CH₂NHCONH 9 1-Methylcyc-Pr HO₂C(CH₂)₂CONH 10 1-Methylcyc-Pr imidazol-1-ylCH₂CONH 11 1-Methylcyc-Pr Morpholin-4-ylCH₂CH₂NHCSNH 12 1-Methylcyc-Pr HO₂CCH₂NHCONH 13 1-Methylcyc-Pr HO₂C(CH₂)₃CONH 14 1-Methylcyc-Pr H₂NCH₂CONH 15 1-Methylcyc-Pr CH₃NHCH₂CONH 16 1-Methylcyc-Pr 4-F-phenylCH₂NHCH₂CONH 17 1-Methylcyc-Pr pyrrolidin-1-ylCH₂CONH 18 1-Methylcyc-Pr pyrid-2-ylCH₂NHCH₂CONH 19 1-Methylcyc-Pr pyrid-3-ylCH₂NHCH₂CONH 20 1-Methylcyc-Pr pyrid-4-ylCH₂NHCH₂CONH 21 1-Methylcyc-Pr BocNHCH₂CH₂NHCH₂CONH 22 1-Methylcyc-Pr HOCH₂CH(CH₃)NHCH₂CONH 23 1-Methylcyc-Pr CH₃CH(OH)CH₂NHCH₂CONH 24 1-Methylcyc-Pr H₂NCH₂CH₂NHCH₂CONH 25 1-Methylcyc-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH 26 1-Methylcyc-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 27 1-Methylcyc-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 28 1-Methylcyc-Pr (CH₃)₂NCH(CH₃)CONH 29 1-Methylcyc-Pr 1-CH₃-L-prolylNH 30 1-Methylcyc-Pr Homopiperazin-1-ylCH₂CONH 31 1-Methylcyc-Pr CH₃CH₂NHCH₂CONH 32 1-Methylcyc-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 33 1-Methylcyc-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH 34 1-Methylcyc-Pr cyclo-C₃H₅NHCH₂CONH 35 1-Methylcyc-Pr Piperidin-4-ylCH₂NHCH₂CONH 36 1-Methylcyc-Pr HO(CH₂)₃NHCH₂CONH 37 1-Methylcyc-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 38 1-Methylcyc-Pr HOCH₂CH₂NHCH₂CONH 39 1-Methylcyc-Pr cyclo-C₄H₇NHCH₂CONH 40 1-Methylcyc-Pr azetidin-3-ylCONH 41 1-Methylcyc-Pr D-prolylNH.HCl 42 1-Methylcyc-Pr Boc-D-prolylNH 43 1-Methylcyc-Pr L-prolylNH.HCl 44 1-Methylcyc-Pr Boc-L-prolylNH 45 1-Methylcyc-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH 46 1-Methylcyc-Pr (CH₃)₂CHNHCH₂CONH 47 1-Methylcyc-Pr BocNHCH₂CH₂CONH 48 1-Methylcyc-Pr piperazin-2-yl-CONH 49 1-Methylcyc-Pr 4-Me-piperazin-2-yl-CONH 50 1-Methylcyc-Pr piperidin-1-ylNHCONH 51 1-Methylcyc-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H 52 1-Methylcyc-Pr pyrid-2-ylNHCONH 53 1-Methylcyc-Pr (CH₃)₂NCH₂CH₂NHCONH 54 1-Methylcyc-Pr BocNHCH₂CH₂NHCONH 55 1-Methylcyc-Pr HO(CH₂)₄NHCONH 56 1-Methylcyc-Pr (CH₃)₂NNHCONH 57 1-Methylcyc-Pr (CH₃)₂N(CH₂)₃NHCONH 58 1-Methylcyc-Pr 1-CH₃-homopiperazin-4-yl-CONH 59 1-Methylcyc-Pr CH₃SO₂NHCONH 60 1-Methylcyc-Pr CH₃ONHCONH 61 1-Methylcyc-Pr (CH₃)₂NCH₂CH₂NHCONH 62 1-Methylcyc-Pr 1-CH₃-piperidin-4-ylN(CH₃)CONH 63 1-Methylcyc-Pr tetrahydrofur-2-ylCH₂NHCONH 64 1-Methylcyc-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH 65 1-Methylcyc-Pr HOCH₂CH(CH₃)NHCONH 66 1-Methylcyc-Pr CH₃CH(CH)CH₂NHCONH 67 1-Methylcyc-Pr HOCH₂CH₂NHCONH 68 1-Methylcyc-Pr morpholin-4-ylNHCONH 69 1-Methylcyc-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH 70 1-Methylcyc-Pr 1-CH₃-piperazin-4-ylNHCONH 71 1-Methylcyc-Pr morpholin-4-ylCH₂CH₂NHCONH 72 1-Methylcyc-Pr 1-CH₃-piperazin-4-ylCONH 73 1-Methylcyc-Pr pyrid-2-ylNHCONH 74 1-Methylcyc-Pr pyrid-4-ylNHCONH 75 1-Methylcyc-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 76 1-Methylcyc-Pr 2-CH₃-piperazin-1-ylCONH 77 1-Methylcyc-Pr 3-CH₃-piperazin-1-ylCH₂CONH 78 1-Methylcyc-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 79 1-Methylcyc-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 80 1-Methylcyc-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 81 1-Methylcyc-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 82 1-Methylcyc-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 83 1-Methylcyc-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 84 1-Methylcyc-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 1-Methylcyc-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

TABLE XXIII (a)

(b)

(c)

Ex. # R² R⁷ 1 i-Bu 1-CH₃-piperazin-4-ylCH₂CONH 2 i-Bu CH₃NHCONH 3 i-Bu morpholin-4-ylCH₂CONH 4 i-Bu azetidin-1-ylCH₂CONH 5 i-Bu (CH₃)₂NCH₂CH₂SO₂NH 6 i-Bu EtO₂CCH₂NHCONH 7 i-Bu Hydantoin-1-yl 8 i-Bu HOCH₂CH₂NHCONH 9 i-Bu HO₂C(CH₂)₂CONH 10 i-Bu imidazol-1-ylCH₂CONH 11 i-Bu Morpholin-4-ylCH₂CH₂NHCSNH 12 i-Bu HO₂CCH₂NHCONH 13 i-Bu HO₂C(CH₂)₃CONH 14 i-Bu H₂NCH₂CONH 15 i-Bu CH₃NHCH₂CONH 16 i-Bu 4-F-phenylCH₂NHCH₂CONH 17 i-Bu pyrrolidin-1-ylCH₂CONH 18 i-Bu pyrid-2-ylCH₂NHCH₂CONH 19 i-Bu pyrid-3-ylCH₂NHCH₂CONH 20 i-Bu pyrid-4-ylCH₂NHCH₂CONH 21 i-Bu BocNHCH₂CH₂NHCH₂CONH 22 i-Bu HOCH₂CH(CH₃)NHCH₂CONH 23 i-Bu CH₃CH(OH)CH₂NHCH₂CONH 24 i-Bu H₂NCH₂CH₂NHCH₂CONH 25 i-Bu morpholin-4-ylCH₂CH₂NHCH₂CONH 26 i-Bu 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 27 i-Bu (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 28 i-Bu (CH₃)₂NCH(CH₃)CONH 29 i-Bu 1-CH₃-L-prolylNH 30 i-Bu Homopiperazin-1-ylCH₂CONH 31 i-Bu CH₃CH₂NHCH₂CONH 32 i-Bu 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 33 i-Bu (CH₃)₂NCH₂CH₂NHCH₂CONH 34 i-Bu cyclo-C₃H₅NHCH₂CONH 35 i-Bu Piperidin-4-ylCH₂NHCH₂CONH 36 i-Bu HO(CH₂)₃NHCH₂CONH 37 i-Bu 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 38 i-Bu HOCH₂CH₂NHCH₂CONH 39 i-Bu cyclo-C₄H₇NHCH₂CONH 40 i-Bu azetidin-3-ylCONH 41 i-Bu D-prolylNH.HCl 42 i-Bu Boc-D-prolylNH 43 i-Bu L-prolylNH.HCl 44 i-Bu Boc-L-prolylNH 45 i-Bu piperidin-1-ylCH₂CH₂NHCH₂CONH 46 i-Bu (CH₃)₂CHNHCH₂CONH 47 i-Bu BocNHCH₂CH₂CONH 48 i-Bu piperazin-2-yl-CONH 49 i-Bu 4-Me-piperazin-2-yl-CONH 50 i-Bu piperidin-1-ylNHCONH 51 i-Bu H₂NCH₂CH₂NHCONH.F₃CCO₂H 52 i-Bu pyrid-2-ylNHCONH 53 i-Bu (CH₃)₂NCH₂CH₂NHCONH 54 i-Bu BocNHCH₂CH₂NHCONH 55 i-Bu HO(CH₂)₄NHCONH 56 i-Bu (CH₃)₂NNHCONH 57 i-Bu (CH₃)₂N(CH₂)₃NHCONH 58 i-Bu 1-CH₃-homopiperazin-4-yl-CONH 59 i-Bu CH₃SO₂NHCONH 60 i-Bu CH₃ONHCONH 61 i-Bu (CH₃)₂NCH₂CH₂NHCONH 62 i-Bu 1-CH₃-piperidin-4-ylN(CH₃)CONH 63 i-Bu tetrahydrofur-2-ylCH₂NHCONH 64 i-Bu CH₃(CH₂)₂CH(OH)CH₂NHCONH 65 i-Bu HOCH₂CH(CH₃)NHCONH 66 i-Bu CH₃CH(OH)CH₂NHCONH 67 i-Bu HOCH₂CH₂NHCONH 68 i-Bu morpholin-4-ylNHCONH 69 i-Bu (CH₃)₂NCH(CH₃)CH₂NHCONH 70 i-Bu 1-CH₃-piperazin-4-ylNHCONH 71 i-Bu morpholin-4-ylCH₂CH₂NHCONH 72 i-Bu 1-CH₃-piperazin-4-ylCONH 73 i-Bu pyrid-2-ylNHCONH 74 i-Bu pyrid-4-ylNHCONH 75 i-Bu pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 76 i-Bu 2-CH₃-piperazin-1-ylCONH 77 i-Bu 3-CH₃-piperazin-1-ylCH₂CONH 78 i-Bu trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 79 i-Bu cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 80 i-Bu cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 81 i-Bu trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 82 i-Bu trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 83 i-Bu (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 84 i-Bu (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 i-Bu 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

TABLE XXIV (a)

(b)

(c)

Ex. # R⁵ R² R⁷ 1 Me Et 1-CH₃-piperazin-4-ylCH₂CONH 2 Me Et CH₃NHCONH 3 Me Et morpholin-4-ylCH₂CONH 4 Me Et azetidin-1-ylCH₂CONH 5 Me Et (CH₃)₂NCH₂CH₂SO₂NH 6 Me Et EtO₂CCH₂NHCONH 7 Me Et Hydantoin-1-yl 8 Me Et HOCH₂CH₂NHCONH 9 Me Et HO₂C(CH₂)₂CONH 10 Me Et imidazol-1-ylCH₂CONH 11 Me Et Morpholin-4-ylCH₂CH₂NHCSNH 12 Me Et HO₂CCH₂NHCONH 13 Me Et HO₂C(CH₂)₃CONH 14 Me Et H₂NCH₂CONH 15 Me Et CH₃NHCH₂CONH 16 Me Et 4-F-phenylCH₂NHCH₂CONH 17 Me Et pyrrolidin-1-ylCH₂CONH 18 Me Et pyrid-2-ylCH₂NHCH₂CONH 19 Me Et pyrid-3-ylCH₂NHCH₂CONH 20 Me Et pyrid-4-ylCH₂NHCH₂CONH 21 Me Et BocNHCH₂CH₂NHCH₂CONH 22 Me Et HOCH₂CH(CH₃)NHCH₂CONH 23 Me Et CH₃CH(OH)CH₂NHCH₂CONH 24 Me Et H₂NCH₂CH₂NHCH₂CONH 25 Me Et morpholin-4-ylCH₂CH₂NHCH₂CONH 26 Me Et 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 27 Me Et (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 28 Me Et (CH₃)₂NCH(CH₃)CONH 29 Me Et 1-CH₃-L-prolylNH 30 Me Et Homopiperazin-1-ylCH₂CONH 31 Me Et CH₃CH₂NHCH₂CONH 32 Me Et 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 33 Me Et (CH₃)₂NCH₂CH₂NHCH₂CONH 34 Me Et cyclo-C₃H₅NHCH₂CONH 35 Me Et Piperidin-4-ylCH₂NHCH₂CONH 36 Me ET HO(CH₂)₃NHCH₂CONH 37 Me Et 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 38 Me ET HOCH₂CH₂NHCH₂CONH 39 Me Et cyclo-C₄H₇NHCH₂CONH 40 Me Et azetidin-3-ylCONH 41 Me Et D-prolylNH.HCl 42 Me Et Boc-D-prolylNH 43 Me Et L-prolylNH.HCl 44 Me Et Boc-L-prolylNH 45 Me Et piperidin-1-ylCH₂CH₂NHCH₂CONH 46 Me Et (CH₃)₂CHNHCH₂CONH 47 Me Et BocNHCH₂CH₂CONH 48 Me Et piperazin-2-yl-CONH 49 Me Et 4-Me-piperazin-2-yl-CONH 50 Me Et piperidin-1-ylNHCONH 51 Me Et H₂NCH₂CH₂NHCONH.F₃CCO₂H 52 Me Et pyrid-2-ylNHCONH 53 Me Et (CH₃)₂NCH₂CH₂NHCONH 54 Me Et BocNHCH₂CH₂NHCONH 55 Me Et HO(CH₂)₄NHCONH 56 Me Et (CH₃)₂NNHCONH 57 Me Et (CH₃)₂N(CH₂)₃NHCONH 58 Me Et 1-CH₃-homopiperazin-4-yl-CONH 59 Me Et CH₃SO₂NHCONH 60 Me Et CH₃ONHCONH 61 Me Et (CH₃)₂NCH₂CH₂NHCONH 62 Me Et 1-CH₃-piperidin-4-ylN(CH₃)CONH 63 Me Et tetrahydrofur-2-ylCH₂NHCONH 64 Me Et CH₃(CH₂)₂CH(OH)CH₂NHCONH 65 Me Et HOCH₂CH(CH₃)NHCONH 66 Me Et CH₃CH(OH)CH₂NHCONH 67 Me Et HOCH₂CH₂NHCONH 68 Me Et morpholin-4-ylNHCONH 69 Me Et (CH₃)₂NCH(CH₃)CH₂NHCONH 70 Me Et 1-CH₃-piperazin-4-ylNHCONH 71 Me Et morpholin-4-ylCH₂CH₂NHCONH 72 Me Et 1-CH₃-piperazin-4-ylCONH 73 Me Et pyrid-2-ylNHCONH 74 Me Et pyrid-4-ylNHCONH 75 Me Et pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 76 Me Et 2-CH₃-piperazin-1-ylCONH 77 Me Et 3-CH₃-piperazin-1-ylCH₂CONH 78 Me Et trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 79 Me Et cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 80 Me Et cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 81 Me Et trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 82 Me Et trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 83 Me Et (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 84 Me Et (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 Me Et 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

TABLE XXV (a)

(b)

(c)

Ex. # R⁵ R² R⁷ 1 Me cyc-Pr 1-CH₃-piperazin-4-ylCH₂CONH 2 Me cyc-Pr CH₃NHCONH 3 Me cyc-Pr morpholin-4-ylCH₂CONH 4 Me cyc-Pr azetidin-1-ylCH₂CONH 5 Me cyc-Pr (CH₃)₂NCH₂CH₂SO₂NH 6 Me cyc-Pr EtO₂CCH₂NHCONH 7 Me cyc-Pr Hydantoin-1-yl 8 Me cyc-Pr HOCH₂CH₂NHCONH 9 Me cyc-Pr HO₂C(CH₂)₂CONH 10 Me cyc-Pr imidazol-1-ylCH₂CONH 11 Me cyc-Pr Morpholin-4-ylCH₂CH₂NHCSNH 12 Me cyc-Pr HO₂CCH₂NHCONH 13 Me cyc-Pr HO₂C(CH₂)₃CONH 14 Me cyc-Pr H₂NCH₂CONH 15 Me cyc-Pr CH₃NHCH₂CONH 16 Me cyc-Pr 4-F-phenylCH₂NHCH₂CONH 17 Me cyc-Pr pyrrolidin-1-ylCH₂CONH 18 Me cyc-Pr pyrid-2-ylCH₂NHCH₂CONH 19 Me cyc-Pr pyrid-3-ylCH₂NHCH₂CONH 20 Me cyc-Pr pyrid-4-ylCH₂NHCH₂CONH 21 Me cyc-Pr BocNHCH₂CH₂NHCH₂CONH 22 Me cyc-Pr HOCH₂CH(CH₃)NHCH₂CONH 23 Me cyc-Pr CH₃CH(OH)CH₂NHCH₂CONH 24 Me cyc-Pr H₂NCH₂CH₂NHCH₂CONH 25 Me cyc-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH 26 Me cyc-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 27 Me cyc-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 28 Me cyc-Pr (CH₃)₂NCH(CH₃)CONH 29 Me cyc-Pr 1-CH₃-L-prolylNH 30 Me cyc-Pr Homopiperazin-1-ylCH₂CONH 31 Me cyc-Pr CH₃CH₂NHCH₂CONH 32 Me cyc-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 33 Me cyc-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH 34 Me cyc-Pr cyclo-C₃H₅NHCH₂CONH 35 Me cyc-Pr Piperidin-4-ylCH₂NHCH₂CONH 36 Me cyc-Pr HO(CH₂)₃NHCH₂CONH 37 Me cyc-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 38 Me cyc-Pr HOCH₂CH₂NHCH₂CONH 39 Me cyc-Pr cyclo-C₄H₇NHCH₂CONH 40 Me cyc-Pr azetidin-3-ylCONH 41 Me cyc-Pr D-prolylNH.HCl 42 Me cyc-Pr Boc-D-prolylNH 43 Me cyc-Pr L-prolylNH.HCl 44 Me cyc-Pr Boc-L-prolylNH 45 Me cyc-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH 46 Me cyc-Pr (CH₃)₂CHNHCH₂CONH 47 Me cyc-Pr BocNHCH₂CH₂CONH 48 Me cyc-Pr piperazin-2-yl-CONH 49 Me cyc-Pr 4-Me-piperazin-2-yl-CONH 50 Me cyc-Pr piperidin-1-ylNHCONH 51 Me cyc-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H 52 Me cyc-Pr pyrid-2-ylNHCONH 53 Me cyc-Pr (CH₃)₂NCH₂CH₂NHCONH 54 Me cyc-Pr BocNHCH₂CH₂NHCONH 55 Me cyc-Pr HO(CH₂)₄NHCONH 56 Me cyc-Pr (CH₃)₂NNHCONH 57 Me cyc-Pr (CH₃)₂N(CH₂)₃NHCONH 58 Me cyc-Pr 1-CH₃-homopiperazin-4-yl-CONH 59 Me cyc-Pr CH₃SO₂NHCONH 60 Me cyc-Pr CH₃ONHCONH 61 Me cyc-Pr (CH₃)₂NCH₂CH₂NHCONH 62 Me cyc-Pr 1-CH₃-piperidin-4-ylN(CH₃)CONH 63 Me cyc-Pr tetrahydrofur-2-ylCH₂NHCONH 64 Me cyc-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH 65 Me cyc-Pr HOCH₂CH(CH₃)NHCONH 66 Me cyc-Pr CH₃CH(OH)CH₂NHCONH 67 Me cyc-Pr HOCH₂CH₂NHCONH 68 Me cyc-Pr morpholin-4-ylNHCONH 69 Me cyc-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH 70 Me cyc-Pr 1-CH₃-piperazin-4-ylNHCONH 71 Me cyc-Pr morpholin-4-ylCH₂CH₂NHCONH 72 Me cyc-Pr 1-CH₃-piperazin-4-ylCONH 73 Me cyc-Pr pyrid-2-ylNHCONH 74 Me cyc-Pr pyrid-4-ylNHCONH 75 Me cyc-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 76 Me cyc-Pr 2-CH₃-piperazin-1-ylCONH 77 Me cyc-Pr 3-CH₃-piperazin-1-ylCH₂CONH 78 Me cyc-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 79 Me cyc-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 80 Me cyc-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 81 Me cyc-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 82 Me cyc-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 83 Me cyc-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 84 Me cyc-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 Me cyc-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

TABLE XXVI (a)

(b)

(c)

Ex. # R⁵ R² R⁷ 1 Me i-Pr 1-CH₃-piperazin-4-ylCH₂CONH 2 Me i-Pr CH₃NHCONH 3 Me i-Pr morpholin-4-ylCH₂CONH 4 Me i-Pr azetidin-1-ylCH₂CONH 5 Me i-Pr (CH₃)₂NCH₂CH₂SO₂NH 6 Me i-Pr EtO₂CCH₂NHCONH 7 Me i-Pr Hydantoin-1-yl 8 Me i-Pr HOCH₂CH₂NHCONH 9 Me i-Pr HO₂C(CH₂)₂CONH 10 Me i-Pr imidazol-1-ylCH₂CONH 11 Me i-Pr Morpholin-4-ylCH₂CH₂NHCSNH 12 Me i-Pr HO₂CCH₂NHCONH 13 Me i-Pr HO₂C(CH₂)₃CONH 14 Me i-Pr H₂NCH₂CONH 15 Me i-Pr CH₃NHCH₂CONH 16 Me i-Pr 4-F-phenylCH₂NHCH₂CONH 17 Me i-Pr pyrrolidin-1-ylCH₂CONH 18 Me i-Pr pyrid-2-ylCH₂NHCH₂CONH 19 Me i-Pr pyrid-3-ylCH₂NHCH₂CONH 20 Me i-Pr pyrid-4-ylCH₂NHCH₂CONH 21 Me i-Pr BocNHCH₂CH₂NHCH₂CONH 22 Me i-Pr HOCH₂CH(CH₃)NHCH₂CONH 23 Me i-Pr CH₃CH(OH)CH₂NHCH₂CONH 24 Me i-Pr H₂NCH₂CH₂NHCH₂CONH 25 Me i-Pr morpholin-4-ylCH₂CH₂NHCH₂CONH 26 Me i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CH₂CONH 27 Me i-Pr (CH₃)₂NCH₂CH₂N(CH₃)CH₂CONH 28 Me i-Pr (CH₃)₂NCH(CH₃)CONH 29 Me i-Pr 1-CH₃-L-prolylNH 30 Me i-Pr Homopiperazin-1-ylCH₂CONH 31 Me i-Pr CH₃CH₂NHCH₂CONH 32 Me i-Pr 4-(CH₂NH₂)piperidin-1-ylCH₂CONH 33 Me i-Pr (CH₃)₂NCH₂CH₂NHCH₂CONH 34 Me i-Pr cyclo-C₃H₅NHCH₂CONH 35 Me i-Pr Piperidin-4-ylCH₂NHCH₂CONH 36 Me i-Pr HO(CH₂)₃NHCH₂CONH 37 Me i-Pr 1-Bocpiperidin-4-ylCH₂NHCH₂CONH 38 Me i-Pr HOCH₂CH₂NHCH₂CONH 39 Me i-Pr cyclo-C₄H₇NHCH₂CONH 40 Me i-Pr azetidin-3-ylCONH 41 Me i-Pr D-prolylNH.HCl 42 Me i-Pr Boc-D-prolylNH 43 Me i-Pr L-prolylNH.HCl 44 Me i-Pr Boc-L-prolylNH 45 Me i-Pr piperidin-1-ylCH₂CH₂NHCH₂CONH 46 Me i-Pr (CH₃)₂CHNHCH₂CONH 47 Me i-Pr BocNHCH₂CH₂CONH 48 Me i-Pr piperazin-2-yl-CONH 49 Me i-Pr 4-Me-piperazin-2-yl-CONH 50 Me i-Pr piperidin-1-ylNHCONH 51 Me i-Pr H₂NCH₂CH₂NHCONH.F₃CCO₂H 52 Me i-Pr pyrid-2-ylNHCONH 53 Me i-Pr (CH₃)₂NCH₂CH₂NHCONH 54 Me i-Pr BocNHCH₂CH₂NHCONH 55 Me i-Pr HO(CH₂)₄NHCONH 56 Me i-Pr (CH₃)₂NNHCONH 57 Me i-Pr (CH₃)₂N(CH₂)₃NHCONH 58 Me i-Pr 1-CH₃-homopiperazin-4-yl-CONH 59 Me i-Pr CH₃SO₂NHCONH 60 Me i-Pr CH₃ONHCONH 61 Me i-Pr (CH₃)₂NCH₂CH₂NHCONH 62 Me i-Pr 1-CH₃-piperidin-4-ylN(CH₃)CONH 63 Me i-Pr tetrahydrofur-2-ylCH₂NHCONH 64 Me i-Pr CH₃(CH₂)₂CH(OH)CH₂NHCONH 65 Me i-Pr HOCH₂CH(CH₃)NHCONH 66 Me i-Pr CH₃CH(OH)CH₂NHCONH 67 Me i-Pr HOCH₂CH₂NHCONH 68 Me i-Pr morpholin-4-ylNHCONH 69 Me i-Pr (CH₃)₂NCH(CH₃)CH₂NHCONH 70 Me i-Pr 1-CH₃-piperazin-4-ylNHCONH 71 Me i-Pr morpholin-4-ylCH₂CH₂NHCONH 72 Me i-Pr 1-CH₃-piperazin-4-ylCONH 73 Me i-Pr pyrid-2-ylNHCONH 74 Me i-Pr pyrid-4-ylNHCONH 75 Me i-Pr pyrrolidin-1-ylCH₂CH₂NHCH₂CONH 76 Me i-Pr 2-CH₃-piperazin-1-ylCONH 77 Me i-Pr 3-CH₃-piperazin-1-ylCH₂CONH 78 Me i-Pr trans-2,5-di-CH₃-piperazin-1-ylCH₂CONH 79 Me i-Pr cis-2,6-di-CH₃-piperazin-1-ylCH₂CONH 80 Me i-Pr cis-3,5-di-CH₃-piperazin-1-ylCH₂CONH 81 Me i-Pr trans-2,6-di-CH₃-piperazin-1-ylCH₂CONH 82 Me i-Pr trans-3,5-di-CH₃-piperazin-1-ylCH₂CONH 83 Me i-Pr (R)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 84 Me i-Pr (S)-1-Ethylpyrrolidin-2-ylCH₂NHCONH 85 Me i-Pr 5-CH₃-pyrazin-2-ylCH₂NHCH₂CONH

UTILITY

Certain analogs were selective for their activity against cyclin dependent kinases and their cyclin bound complexes and were less active against other known serine/threonine kinases such as Protein Kinase A (PKA) and Protein Kinase C (PKC). In addition, these inhibitors were less active against tyrosine kinases such as c-Abl.

Inhibition of Kinase/Cyclin Complex Enzymatic Activity

Several of the compounds disclosed in this invention were assayed for their inhibitory activity against cyclin dependent kinase4/D1, cyclin dependent kinase1/B kinase, cyclin dependent kinase2/A kinase, and cyclin dependent kinase2/E kinase complexes. Briefly, the in vitro assays employ cell lysates from insect cells expressing either of the kinases and subsequently their corresponding regulatory units. The cyclin dependent kinase2/cyclinE is purified from insect cells expressing His-tagged cyclin dependent kinase 2 and cyclin E. The cyclin dependent kinase/cyclin lysate is combined in a microtitre-type plate along with a kinase compatible buffer, ³²P-labeled ATP at a concentration of 50 mM, a GST-Rb fusion protein and the test compound at varying concentrations. The kinase reaction is allowed to proceeded with the radiolabled ATP, then effectively stopped by the addition of a large excess of EDTA and unlabeled ATP. The GST-Rb labeled protein is sequestered on a GSH-Sepharose bead suspension, washed, resuspended in scintillant, and the ³²P activity detected in a scintillation counter. The compound concentration which inhibits 50% of the kinase activity was calculated for each compound. A compound was considered active if its IC₅₀ was found to be less than 1 μM.

Inhibition of HCT 116 Cancer Cell Proliferation

To test the cellular activity of several compounds disclosed in this invention, we examined the effect of these compounds on cultured HCT116 cells and determined their effect on cell-cycle progression by the calorimetric cytotoxcity test using sulforhodamine B (Skehan et al. J. Natl. Cancer Inst. 82:1107-12, 1990). Briefly, HCT116 cells are cultured in the presence of test compounds at increasing concentrations. At selected time points, groups of cells are fixed with trichloroacetic acid and stained with sulforhodamine B (SRB). Unbound dye was removed by washing and protein-bound dye was extracted for determination of optical density. A compound was considered active if its IC₅₀ was found to be less than 10 μM. 

What is claimed is:
 1. A compound of formula (I) or its

tautomer, formula (II): or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein: Q is selected from the group: H, OH, and CH₃, and CH₂CH₃; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR⁶; R¹ is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-3 R⁷; R² is selected from the group: C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S—C₁₋₃ alkyl, O—C₁₋₃ alkyl, NH₂, NH—C₁₋₃ alkyl, N(C₁₋₂ alkyl)₂, OCF₃, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH₂CN, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NHC₁₋₃ alkyl, CH₂NMe₂, CF₃, CHO, OCH₂CH₂OH, OCH(Me)CH₂OH, OCH₂CH(Me)OH, OCH₂CH₂NMe₂, and CHF₂; R³ is selected from the group: H, F, Cl, Br, I, CF₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, CH═CHR^(a), C₁₋₃ alkyl, C₁₋₃ alkoxy, CO₂H, CONH₂. CONH(C₁₋₃ alkyl), CON(C₁₋₃ alkyl)₂, CO₂C₁₋₃ alkyl, C(O)C₁₋₂ alkyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; R⁴ is selected from the group: H, F, Cl, Br, I, CF₃, C₁₋₃ alkyl, C₂₋₃ alkenyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; R⁵ is selected from the group: H, C₁₋₃ alkyl, F, Cl, Br, I, CF₃, and C₂₋₃ alkenyl; wherein when Z is C, Q is H, R¹ is phenyl substituted with C₁₋₄ alkyl, hydroxy, alkoxy, amino, substituted amino, mercapto, halogen, trifluoromethyl or nitro, then either R² is selected from the group: C₂₋₄ alkenyl, C₂₋₄ alkynyl, S—C₁₋₃ alkyl, O—C₁₋₃ alkyl, NH₂, NH—C₁₋₃ alkyl, N(C₁₋₂ alkyl)₂, OCF₃, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH₂CN, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NHC₁₋₃ alkyl, CH₂NMe₂, CF₃, CHO, OCH₂CH₂OH, OCH(Me)CH₂OH, OCH₂CH(Me)OH, OCH₂CH₂NMe₂, and CHF₂; or, R³ is selected from the group consisting of: CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, CH═CHR^(a), CO₂H, CONH₂, CONH(C₁₋₃ alkyl), CON(C₁₋₃ alkyl)₂, CO₂C₁₋₃ alkyl, C(O)C₁₋₂ alkyl, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂ and alkenyl; or, R⁴ is selected from the group consisting of C₂₋₃ alkenyl; or, R⁵ is selected from the group consisting of C₂₋₃ alkenyl; R⁶ is selected from the group: H, F, Cl, Br, I, CF₃, —NO₂, C₁₋₃ alkyl optionally substituted with 1-2 R, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, CO₂H, CHO, CONR^(a)R^(b), CO₂C₁₋₃ alkyl, C(O)C₁₋₂ alkyl, CH₂NHR^(a), CONR^(g)NR^(a)R^(b), NR^(a)R^(b); SO₂NR^(a)R^(b), CR═NNR^(a)R^(b), CR═NOR^(f), and R^(h); R⁷ is independently, at each occurrence, selected from the group: OH, C₁₋₆ alkoxy, OC₂₋₆ alkyl-CO₂H, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, I, CF₃, OCF₃, —CN, —NO₂, CO₂H, CO₂(C₁₋₆ alkyl), CONR^(a)R^(b), NR^(g)CONHOR^(g), NR^(g)CONHSO₂R^(a), NHNR^(g)C(O)OR^(a), NR^(g)C(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, —SO₂NR^(a)R^(b), NHSO₂NHCO₂C₁₋₄ alkyl, NR^(g)SO₂NR^(a)R^(b), NR^(g)SO₂CHR^(e)CH₂NR^(a)R^(b), NR^(g)COCHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)NR^(b)CH₂R^(f)R^(a), NR^(g)COCH₂CHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)CH₂NR^(a)R^(b), NR^(g)CO(CH₂)_(m)NR^(a)R^(b), NR^(g)CONR^(e)(CH₂)_(n)NR^(a)R^(b), NR^(g)CO₂(CHR^(e))NR^(a)R^(b), CONR^(e)NR^(a)R^(b), NR^(g)CONR^(e)NR^(a)R^(b), C₃₋₁₀ carbocycle, C₁₋₁₀ alkyl substituted with 0-3 R⁸, NHCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₂₋₁₀ alkenyl substituted with 0-3 R⁸, C₂₋₁₀ alkynyl substituted with 0-3 R⁸, and C₃₋₁₀ heterocycle containing 1-4 heteroatoms selected from O, N, and S; R⁸ is independently, at each occurrence, selected from the group: ═O, OH, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, F, Cl, Br, I, CO₂H, COR^(a), CO₂(benzyl), CO₂(C₁₋₆ alkyl), and CONR^(a)R^(b); R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₁₋₆ alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, CO₂H, OH, and NR^(c)R^(d); R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R^(c) is independently, at each occurrence selected from the group: H, R^(f), and CO₂H; R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe; R^(g) is independently, at each occurrence, selected from H and C₁₋₃ alkyl; R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and
 6. 2. A compound according to claim 1, wherein: Q is selected from the group: H, OH, and CH₃; Y is selected from the group: F, Cl, and Br; Z is selected from the group: N and CR⁶; R¹ is selected from the group: phenyl and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-3 R⁷; R² is selected from the group: C₂₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S—C₁₋₂ alkyl, O—C₁₋₂ alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, CH₂CN, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NMe₂, CF₃, and CHO; R³ is independently selected from the group: H, F, Cl, CH₃, CH₂CH₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, and CH═CHR^(a), R⁴ is independently selected from the group: H, F, Cl, and CH₃; R⁵ is independently selected from the group: H, CH₃, F, Cl, Br, and CF₃; R⁶ is independently selected from the group: H, F, Cl, Br, CF₃, C₁₋₃ alkyl optionally substituted with R, CO₂H, CONH₂, CONHR^(a), CONHNR^(a)R^(b), CHO, CH₃, SO₂NR^(a)R^(b); phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH₂NHR^(a); R⁷ is independently, at each occurrence, selected from the group: OH, C₁₋₃ alkoxy, OC₂₋₆alkyl-CO₂H, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, I, CF₃, OCF₃, —CN, CO₂(C₁₋₆ alkyl), CONR^(a)R^(b), NR^(g)C(O)OR^(a), NR^(g)C(O)NR^(a)R^(b), NR^(g)CONHOR^(g), NR^(g)CONHSO₂R^(a), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, SO₂NR^(a)R^(b), NR^(g)SO₂NR^(a)R^(b), NR^(g)SO₂NHCO₂C₁₋₄ alkyl, NR^(g)SO₂CHR^(e)CH₂NR^(a)R^(b), NR^(g)COCHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)NR^(b)CH₂R^(f)R^(a), NR^(g)COCH₂CHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)CH₂NR^(a)R^(b), NR^(g)CO(CH₂)_(m)NR^(a)R^(b), NR^(g)CONR^(e)(CH₂)_(n)NR^(a)R^(b), NR^(g)CO₂(CHR^(e))_(n)NR^(a)R^(b), CONR^(e)NR^(a)R^(b), NR^(g)CONR^(e)NR^(a)R^(b), C₃₋₇ carbocycle, NHCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₁₋₁₀ alkyl substituted with 0-3 R⁸, C₂₋₆ alkenyl substituted with 0-3 R⁸, C₂₋₆ alkynyl substituted with 0-2 R⁸, and C₃₋₇ heterocycle containing 1-3 heteroatoms selected from O, N, and S; R⁸ is independently, at each occurrence, selected from the group: ═O, OH, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, COR^(a), and CONR^(a)R^(b); R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₁₋₆ alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, CO₂H, and NR^(c)R^(d); R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing an additional 0-1 N, O, or S atom; alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R^(c) is independently, at each occurence, selected from the group: H, R^(f), and CO₂H; R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₄ alkyl; R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe; R^(g) is independently, at each occurrence, selected from H and C₁₋₃ alkyl; R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and
 6. 3. A compound according to claim 2, wherein: Q is H; Y is selected from the group: F, Cl, and Br; Z is CR⁶; R¹ is selected from the group: phenyl, pyridyl, pyrazyl pyrimidyl, pyridazyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, and a 5 membered aromatic heterocycle containing 1-2 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-2 R⁷; R² is selected from the group: C₂₋₄ alkyl, cyclopropyl, cyclobutyl, 1-methylcyclopropyl, and CF₃; R³ is independently selected from the group: H, F, CH₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, and CH═CHR^(a); R⁴ is independently selected from the group: H and F; R⁵ is independently selected from the group: CH₃, F, Cl, and Br; R⁶ is independently selected from the group: H, F, Cl, Br, CF₃, CH₃, CONH₂, CONHR^(a), CONHNR^(a)R^(b), SO₂NR^(a)R^(b); CH₂OH, CHO, phenyl, and heteroaryl having 5-6 atoms in the ring and containing 1-2 N, O, or S atoms; and CH₂NHR^(a); R⁷ is independently, at each occurrence, selected from the group: OH, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, CF₃, —CN, CONR^(a)R^(b), NHC(O)OR^(a), NHC(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, SO₂NR^(a)R^(b), NHSO₂NR^(a)R^(b), NHCONHOR^(e), NHCONHSO₂R^(f), NHSO₂NHCO₂C₁₋₄ alkyl, NHSO₂CHR^(e)CH₂NR^(a)R^(b), NHCOCHR^(e)NR^(a)R^(b), NHCOCHR^(e)NR^(b)CH₂R^(f)R^(a), NHCOCH₂CHR^(e)NR^(a)R^(b), NHCOCHR^(e)CH₂NR^(a)R^(b), NHCO(CH₂)_(m)NR^(a)R^(b), NHCONR^(e)(CH₂)_(n)NR^(a)R^(b), NHCO₂(CHR^(e))_(n)NNR^(a)R^(b), CONR^(e)NR^(a)R^(b), NHCONR^(e)NR^(a)R^(b), NHCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₃₋₇ carbocycle, C₁₋₆ alkyl substituted with 0-3 R⁸, C₂₋₆ alkenyl substituted with 0-3 R⁸, C₂₋₆ alkynyl substituted with 0-3 R⁸, and C₃₋₇ heterocycle containing 1-3 heteroatoms selected from O, N, and S; R⁸ is independently, at each occurrence, selected from the group: OH, C₁₋₃ alkoxy, NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, and CONR^(a)R^(b); R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, and C₁₋₆ alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, and NR^(c)R^(d); R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R^(c) is independently, at each occurrence, selected from the group: H and R^(f); R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-2 additional N, S, or O atoms; R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₃alkyl; R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe; R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and
 6. 4. A compound according to claim 3 wherein: Q is H; Y is Cl; Z is CR⁶; R¹ is selected from the group: phenyl, pyridyl, pyrrolyl, furyl, thienyl, indazolyl, benzoxazolyl, and benzothiazolyl, and R¹ is substituted with 0-2 R⁷; R² is selected from the group: CF₃, C₂₋₃ alkyl and cyclopropyl; R³ is selected from the group: H, CH₃, CH₂OH, and CHO; R⁴ is H; R⁵ is independently selected from the group: CH₃, F, Cl, and Br; R⁶ is independently selected from the group: H, F, Cl, Br, CH₃, CONH₂, CONHNR^(a)R^(b), SO₂NR^(a)R^(b); CH₂OH, CHO, CH₂NHR^(a), and CONHR^(a); R⁷ is independently, at each occurrence, selected from the group: OH, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, NHC(O)OR^(a), NHC(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, CONR^(a)R^(b), NHCONHOR^(e), NHCONHSO₂R^(f), NHSO₂NHCO₂C₁₋₄ alkyl, NHSO₂CHR^(e)CH₂NR^(a)R^(b), NHCOCHR^(e)NR^(a)R^(b), NHCOCHR^(e)NR^(b)CH₂R^(f)R^(a), NHCOCH₂CHR^(e)NR^(a)R^(b), NHCOCHR^(e)CH₂NR^(a)R^(b), NHCO(CH₂)_(m)NR^(a)R^(b), NHCONR^(e)(CH₂)_(n)NR^(a)R^(b), NHCO₂(CHR^(e))_(n)NNR^(a)R^(b), CONR^(e)NR^(a)R^(b), NHCONHNR^(a)R^(b), C₁₋₄ alkyl substituted with 0-1 R⁸, and C₅₋₇ heterocycle containing 1-3 heteroatoms selected from O, N, and S; R⁸ is independently, at each occurrence, selected from the group: NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, and CONR^(a)R^(b); R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, and C₁₋₃ alkyl substituted with R; R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, and NR^(c)R^(d); R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicyclic heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R^(c) is independently, at each occurrence, selected from the group: H and R^(f); R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₃ alkyl; alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-6 membered ring and containing 0-2 additional N, S, or O atoms; R^(e) is independently, at each occurence, selected from the group: H and CH₃; R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH, and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and
 6. 5. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1-4.
 6. A method of inhibiting cyclin dependent kinase comprising: administering to a host in need of such treatment a therapeutically effective amount of a first compound of formula (I) or its tautomer, formula (II):

or a steroisomer or pharmaceutically acceptable salt form thereof, wherein: Q is selected from the group: H, OH, and CH₃, and CH₂CH₃; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR⁶; R¹ is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-3 R⁷; R² is selected from the group: C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S—C₁₋₃ alkyl, O—C₁₋₃ alkyl, NH₂, NH—C₁₋₃ alkyl, N(C₁₋₂ alkyl)₂, OCF₃, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH₂CN, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NHC₁₋₃ alkyl, CH₂NMe₂, CF₃, CHO, OCH₂CH₂OH, OCH(Me)CH₂OH, OCH₂CH(Me)OH, OCH₂CH₂NMe₂, and CHF₂; R³ is selected from the group: H, F, Cl, Br, I, CF₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, CH═CHR^(a), C₁₋₃ alkyl, C₁₋₃alkoxy, CO₂H, CONH₂, CONH(C₁₋₃ alkyl), CON(C₁₋₃ alkyl)₂, CO₂C₁₋₃ alkyl, C(O)C₁₋₂ akyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; R⁴ is selected from the group: H, F, Cl, Br, I, CF₃, C₁₋₃ alkyl, C₂₋₃ alkenyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; R⁵ is selected from the group: H, C₁₋₃ alkyl, F, Cl, Br, I, CF₃, and C₂₋₃ alkenyl; R⁶ is selected from the group: H, F, Cl, Br, I, CF₃, —NO₂, C₁₋₃ alkyl optionally substituted with 1-2 R, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, CO₂H, CHO, CONR^(a)R^(b), CO₂C₁₋₃ alkyl, C(O)C₁₋₂ alkyl, CH₂NHR^(a), CONR^(g)NR^(a)R^(b), NR^(a)R^(b); SO₂NR^(a)R^(b), CR═NNR^(a)R^(b), CR═NOR^(f), and R^(h); R⁷ is independently, at each occurrence, selected from the group: OH, C₁₋₆ alkoxy, OC₂₋₆ alkyl-CO₂H, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, I, CF₃, OCF₃, —CN, —NO₂, CO₂H, CO₂(C₁₋₆ alkyl), CONR^(a)R^(b), NR^(g)CONHOR^(g), NR^(g)CONHSO₂R^(a), NHNR^(g)C(O)OR^(a), NR^(g)C(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, —SO₂NR^(a)R^(b), NHSO₂NHCO₂C₁₋₄ alkyl, NR^(g)SO₂NR^(a)R^(b), NR^(g)SO₂CHR^(e)CH₂NR^(a)R^(b), NR^(g)COCHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)NR^(b)CH₂R^(f)R^(a), NRgCOCH2CHReNRaRb, NR^(g)COCHR^(e)CH₂NR^(a)R^(b), NR^(g)CO(CH₂)_(m)NR^(a)R^(b), NR^(g)CONR^(e)(CH₂)_(n)NR^(a)R^(b), NR^(g)CO₂(CHR^(e))_(n)NR^(a)R^(b), CONR^(e)NR^(a)R^(b), NR^(g)CONR^(e)NR^(a)R^(b), C₃₋₁₀ carbocycle, C₁₋₁₀ alkyl substituted with 0-3 R⁸, NCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₂₋₁₀ alkenyl substituted with 0-3 R⁸, C₂₋₁₀ alkynyl substituted with 0-3 R⁸, and C₃₋₁₀ heterocycle containing 1-4 heteroatoms selected from O, N, and S; R⁸ is independently, at each occurrence, selected from the group: ═O, OH, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, F, Cl, Br, I, CO₂H, COR^(a), CO₂(benzyl), CO₂(C₁₋₆ alkyl), and CONR^(a)R^(b); R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₁₋₆ alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, CO₂H, OH, and NR^(c)R^(d); R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(a) and R^(b) or R^(a)and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicycle heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R^(c) is independently, at each occurrence, selected from the group: H, R^(f), and CO₂H; R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH and OMe; R^(g) is independently, at each occurrence, selected from H and C₁₋₃ alkyl; R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6; or a pharmaceutically acceptable salt thereof.
 7. A method of inhibiting cyclin dependent kinase according to claim 6 further comprising the administration of a therapeutically effective amount of one or more additional compounds selected from the group of consisting of anti-cancer agents and anti-proliferative agents.
 8. A method of inhibiting cyclin dependent kinase according to claim 7 wherein the anti cancer or anti proliferative agent is selected from the group consisting of: altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxorubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, octreotide, estramustine, and hydroxyurea.
 9. A method of treating cyclin dependent kinase-associated disorders comprising: administering to a host in need of such treatment a therapeutically effective amount of a first compound of formula (I) or its tautomer, formula (II):

or a steroisomer or pharmaceutically acceptable salt form thereof, wherein: Q is selected from the group: H, OH, and CH₃, and CH₂CH₃; Y is selected from the group: F, Cl, Br, and I; Z is selected from the group: N and CR⁶; R¹ is selected from the group: phenyl, tropone, naphthyl, and a 5-10 membered aromatic heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and R¹ is substituted with 0-3 R⁷; R² is selected from the group: C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, S—C₁₋₃ alkyl, O—C₁₋₃ alkyl, NH₂, NH—C₁₋₃ alkyl, N(C₁₋₂ alkyl)₂, OCF₃, cyclopropyl, cyclobutyl, cyclopropylmethyl, cyclobutylmethyl, 1-methylcyclopropyl, 1-methylcyclobutyl, CH₂CN, CH₂OH, CH₂OCH₃, CH₂NH₂, CH₂NHC₁₋₃ alkyl, CH₂NMe₂, CF₃, CHO, OCH₂CH₂OH, OCH(Me)CH₂OH, OCH₂CH(Me)OH, OCH₂CH₂NMe₂, and CHF₂; R³ is selected from the group: H, F, Cl, Br, I, CF₃, CHO, CHR^(g)OH, COCF₃, CH═NOH, CH═NOCH₃, CH═NNH₂, CH═NNHMe, CH═NNMe₂, CH═CHR^(a), C₁₋₃ alkyl, C₁₋₃ alkoxy, CO₂H, CONH₂, CONH(C₁₋₃ alkyl), CON(C₁₋₃ alkyl)₂, CO₂C₁₋₃ alkyl, C(O)C₁₋₂ akyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; R⁴ is selected from the group: H, F, Cl, Br, I, CF₃, C₁₋₃ alkyl, C₂₋₃ alkenyl, NH₂, NH(C₁₋₃ alkyl), and N(C₁₋₃ alkyl)₂; R⁵ is selected from the group: H, C₁₋₃ alkyl, F, Cl, Br, I, CF₃, and C₂₋₃ alkenyl; R⁶ is selected from the group: H, F, Cl, Br, I, CF₃, —NO₂, C₁₋₃ alkyl optionally substituted with 1-2 R, C₂₋₃ alkenyl, C₂₋₃ alkynyl, C₁₋₃ alkoxy, CO₂H, CHO, CONR^(a)R^(b), CO₂C₁₋₃ alkyl, C(O)C₁₋₂ alkyl, CH₂NHR^(a), CONR^(g)NR^(a)R^(b), NR^(a)R^(b); SO₂NNR^(a)R^(b), CR═NNR^(a)R^(b), CR═NOR^(f), and R^(h); R⁷ is independently, at each occurrence, selected from the group: OH, C₁₋₆ alkoxy, OC₂₋₆ alkyl-CO₂H, O—C₂₋₆-alkyl-NR^(a)R^(b), F, Cl, Br, I, CF₃, OCF₃, —CN, —NO₂, CO₂H, CO₂(C₁₋₆ alkyl), CONR^(a)R^(b), NR^(g)CONHOR^(g), NR^(g)CONHSO₂R^(a), NHNR^(g)C(O)OR^(a), NR^(g)C(O)NR^(a)R^(b), NH₂, NH(C₁₋₃ alkyl), N(C₁₋₃ alkyl), N(C₁₋₃ alkyl)₂, —SO₂NR^(a)R^(b), NHSO₂NHCO₂C₁₋₄ alkyl, NR^(g)SO₂NR^(a)R^(b), NR^(g)SO₂CHR^(e)CH₂NNR^(a)R^(b), NR^(g)COCHR^(e)NNR^(a)R^(b), NR^(g)COCHR^(e)NR^(b)CH₂R^(f)R^(a), NR^(g)COCH₂CHR^(e)NR^(a)R^(b), NR^(g)COCHR^(e)CH₂NR^(a)R^(b), NR^(g)CO(CH₂)_(m)NR^(a)R^(b), NR^(g)CONR^(e)(CH₂)_(n)NR^(a)R^(b), NR^(g)CO₂(CHR^(e))_(n)NR^(a)R^(b), CONR^(e)NR^(a)R^(b), NR^(g)CONR^(e)NR^(a)R^(b), C₃₋₁₀ carbocycle, C₁₋₁₀ alkyl substituted with 0-3 R⁸, NCONR^(h), NHCONHCH₂R^(h), NHCOR^(h), NHCOCH₂R^(h), C₂₋₁₀ alkenyl substituted with 0-3 R⁸, C₂₋₁₀ alkynyl substituted with 0-3 R⁸, and C₃₋₁₀ heterocycle containing 1-4 heteroatoms selected from O, N, and S; R⁸ is independently, at each occurrence, selected from the group: ═O, OH, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, NH₂, NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, F, Cl, Br, I, CO₂H, COR^(a), CO₂(benzyl), CO₂(C₁₋₆ alkyl), and CONR^(a)R^(b); R^(a) is independently, at each occurrence, selected from the group: H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, and C₁₋₆ alkyl substituted with one R; R is independently, at each occurrence, selected from the group: H, C₁₋₃ alkyl, C₃₋₆ cycloalkyl, CO₂H, OH, and NR^(c)R^(d); R^(b) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(a) and R^(b) or R^(a) and R^(e), together with the atoms to which they are attached, form a heterocycle having 5-7 atoms in the ring and containing 0-1 additional N, O, or S atom; alternatively, R^(a) and R^(b) and R^(e), together with the atoms to which they are attached, form a bicycle heterocycle having 9-11 atoms in the ring and containing one additional N, S, or O atom; R^(c) is independently, at each occurrence, selected from the group: H, R^(f), and CO₂H; R^(d) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; alternatively, R^(c) and R^(d), together with the atoms to which they are attached, form a 5-7 membered ring and containing 0-3 additional N, S, or O atoms; R^(e) is independently, at each occurrence, selected from the group: H and C₁₋₆ alkyl; R^(f) is C₁₋₄ alkyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH and OMe; R^(g) is independently, at each occurrence, selected from H and C₁₋₃ alkyl; R^(h) is 5-6 membered mononuclear heteroaryl ring or phenyl substituted with 0-1 group selected from the group: NH₂, NHMe, NMe₂, OH and OMe; n at each occurrence is independently selected from 2, 3, 4, 5, and 6; and m at each occurrence is independently selected from 3, 4, 5, and 6; or a pharmaceutically acceptable salt thereof. 